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1
Somogyi, Peter, and Thomas Klausberger. "Defined types of cortical interneurone structure space and spike timing in the hippocampus." Journal of Physiology 562, no. 1 (December 22, 2004): 9–26. http://dx.doi.org/10.1113/jphysiol.2004.078915.
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Yang, Panzao, Joanne O. Davidson, Tania M. Fowke, Robert Galinsky, Guido Wassink, Rashika N. Karunasinghe, Jaya D. Prasad, et al. "Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep." International Journal of Molecular Sciences 21, no. 18 (September 4, 2020): 6475. http://dx.doi.org/10.3390/ijms21186475.
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Perinatal hypoxia-ischemia is associated with disruption of cortical gamma-aminobutyric acid (GABA)ergic interneurons and their surrounding perineuronal nets, which may contribute to persisting neurological deficits. Blockade of connexin43 hemichannels using a mimetic peptide can alleviate seizures and injury after hypoxia-ischemia. In this study, we tested the hypothesis that connexin43 hemichannel blockade improves the integrity of cortical interneurons and perineuronal nets. Term-equivalent fetal sheep received 30 min of bilateral carotid artery occlusion, recovery for 90 min, followed by a 25-h intracerebroventricular infusion of vehicle or a mimetic peptide that blocks connexin hemichannels or by a sham ischemia + vehicle infusion. Brain tissues were stained for interneuronal markers or perineuronal nets. Cerebral ischemia was associated with loss of cortical interneurons and perineuronal nets. The mimetic peptide infusion reduced loss of glutamic acid decarboxylase-, calretinin-, and parvalbumin-expressing interneurons and perineuronal nets. The interneuron and perineuronal net densities were negatively correlated with total seizure burden after ischemia. These data suggest that the opening of connexin43 hemichannels after perinatal hypoxia-ischemia causes loss of cortical interneurons and perineuronal nets and that this exacerbates seizures. Connexin43 hemichannel blockade may be an effective strategy to attenuate seizures and may improve long-term neurological outcomes after perinatal hypoxia-ischemia.
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Qiu, Fang, Xingfeng Mao, Penglai Liu, Jinyun Wu, Yuan Zhang, Daijing Sun, Yueyan Zhu, et al. "microRNA Deficiency in VIP+ Interneurons Leads to Cortical Circuit Dysfunction." Cerebral Cortex 30, no. 4 (November 4, 2019): 2229–49. http://dx.doi.org/10.1093/cercor/bhz236.
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Abstract Genetically distinct GABAergic interneuron subtypes play diverse roles in cortical circuits. Previous studies revealed that microRNAs (miRNAs) are differentially expressed in cortical interneuron subtypes, and are essential for the normal migration, maturation, and survival of medial ganglionic eminence-derived interneuron subtypes. How miRNAs function in vasoactive intestinal peptide expressing (VIP+) interneurons derived from the caudal ganglionic eminence remains elusive. Here, we conditionally removed Dicer in postmitotic VIP+ interneurons to block miRNA biogenesis. We found that the intrinsic and synaptic properties of VIP+ interneurons and pyramidal neurons were concordantly affected prior to a progressive loss of VIP+ interneurons. In vivo recording further revealed elevated cortical local field potential power. Mutant mice had a shorter life span but exhibited better spatial working memory and motor coordination. Our results demonstrate that miRNAs are indispensable for the function and survival of VIP+ interneurons, and highlight a key role of VIP+ interneurons in cortical circuits.
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Fishell, Gord, and Adam Kepecs. "Interneuron Types as Attractors and Controllers." Annual Review of Neuroscience 43, no. 1 (July 8, 2020): 1–30. http://dx.doi.org/10.1146/annurev-neuro-070918-050421.
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Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role in cortical processing. Here, we revisit the question of how to codify their diversity based upon their division of labor and function as controllers of cortical information flow. We suggest that developmental trajectories provide a guide for appreciating interneuron diversity and argue that subtype identity is generated using a configurational (rather than combinatorial) code of transcription factors that produce attractor states in the underlying gene regulatory network. We present our updated three-stage model for interneuron specification: an initial cardinal step, allocating interneurons into a few major classes, followed by definitive refinement, creating subclasses upon settling within the cortex, and lastly, state determination, reflecting the incorporation of interneurons into functional circuit ensembles. We close by discussing findings indicating that major interneuron classes are both evolutionarily ancient and conserved. We propose that the complexity of cortical circuits is generated by phylogenetically old interneuron types, complemented by an evolutionary increase in principal neuron diversity. This suggests that a natural neurobiological definition of interneuron types might be derived from a match between their developmental origin and computational function.
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Lukomska, Agnieszka, Grzegorz Dobrzanski, Monika Liguz-Lecznar, and Malgorzata Kossut. "Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex." Brain Structure and Function 225, no. 1 (December 23, 2019): 387–401. http://dx.doi.org/10.1007/s00429-019-02011-7.
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AbstractInhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80–90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.
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Ying, Guoxin, Sen Wu, Ruiqing Hou, Wei Huang, Mario R. Capecchi, and Qiang Wu. "The Protocadherin Gene Celsr3 Is Required for Interneuron Migration in the Mouse Forebrain." Molecular and Cellular Biology 29, no. 11 (March 30, 2009): 3045–61. http://dx.doi.org/10.1128/mcb.00011-09.
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ABSTRACT Interneurons are extremely diverse in the mammalian brain and provide an essential balance for functional neural circuitry. The vast majority of murine cortical interneurons are generated in the subpallium and migrate tangentially over a long distance to acquire their final positions. By using a mouse line with a deletion of the Celsr3 (Flamingo, or Fmi1) gene and a knock-in of the green fluorescent protein reporter, we find that Celsr3, a member of the nonclustered protocadherin (Pcdh) family, is predominantly expressed in the cortical interneurons in adults and in the interneuron germinal zones in embryos. We show that Celsr3 is crucial for interneuron migration in the developing mouse forebrain. Specifically, in Celsr3 knockout mice, calretinin-positive interneurons are reduced in the developing neocortex, accumulated in the corticostriatal boundary, and increased in the striatum. Moreover, the laminar distribution of cortical calbindin-positive cells is altered. Finally, we found that expression patterns of NRG1 (neuregulin-1) and its receptor ErbB4, which are essential for interneuron migration, are changed in Celsr3 mutants. These results demonstrate that the protocadherin Celsr3 gene is essential for both tangential and radial interneuron migrations in a class-specific manner.
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Lamsa, Karri, and Tomi Taira. "Use-Dependent Shift From Inhibitory to Excitatory GABAA Receptor Action in SP-O Interneurons in the Rat Hippocampal CA3 Area." Journal of Neurophysiology 90, no. 3 (September 2003): 1983–95. http://dx.doi.org/10.1152/jn.00060.2003.
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Cortical inhibitory interneurons set the pace of synchronous neuronal oscillations implicated in synaptic plasticity and various cognitive functions. The hyperpolarizing nature of inhibitory postsynaptic potentials (IPSPs) in interneurons has been considered crucial for the generation of oscillations at β (15–30 Hz) and γ (30–100 Hz) frequency. Hippocampal basket cells and axo-axonic cells in stratum pyramidale-oriens (S-PO) play a central role in the synchronization of the local interneuronal network as well as in pacing of glutamatergic principal cell firing. A lack of conventional forms of plasticity in excitatory synapses onto interneurons facilitates their function as stable neuronal oscillators. We have used gramicidin-perforated and whole cell clamp recordings to study properties of GABAAR-mediated transmission in CA3 SP-O interneurons and in CA3 pyramidal cells in rat hippocampal slices during electrical 5- to 100-Hz stimulation and during spontaneous activity. We show that GABAergic synapses onto SP-O interneurons can easily switch their mode from inhibitory to excitatory during heightened activity. This is based on a depolarizing shift in the GABAA reversal potential ( EGABA-A), which is much faster and more pronounced in interneurons than in pyramidal cells. We also found that the shift in interneuronal function was frequency dependent, being most prominent at 20- to 40-Hz activation of the GABAergic synapses. After 40-Hz tetanic stimulation (100 pulses), GABAA responses remained depolarizing for ∼45 s in the interneurons, promoting bursting in the GABAergic network. Hyperpolarizing EGABA-A was restored >60 s after the stimulus train. Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 μM) to slices. A shift to depolarizing IPSPs by the GABAAR permeant weak acid anion formate provoked interneuronal population bursting, supporting the role of GABAergic excitation in burst generation. Furthermore, depolarizing GABAergic potentials and synchronous interneuronal bursting were enhanced by pentobarbital (100 μM), a positive allosteric modulator of GABAARs, and were blocked by picrotoxin (100 μM). Intriguingly, GABAergic bursts displayed short (<1 s) oscillations at 15–40 Hz, even though only depolarizing GABAA responses were seen in the SP-O interneurons. This β-γ rhythmicity in the interneuron network was dependent on electrotonic coupling, and was abolished by blockade of gap junctions with carbenoxolone (200 μM). Results here implicate the rapid activity-dependent degradation of hyperpolarizing IPSPs in SP-O interneurons in setting the temporal limits for a given interneuron to participate in β-γ oscillations synchronized by GABAergic synapses. Furthermore, they imply that mutual GABAergic excitation provided by interneurons may be an integral part in the function of neuronal networks. We suggest that the use-dependent change in EGABA-A could represent a form of short-term plasticity in interneurons promoting coherent and sustained activation of local GABAergic networks.
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Howard, MacKenzie A., and Scott C. Baraban. "Synaptic integration of transplanted interneuron progenitor cells into native cortical networks." Journal of Neurophysiology 116, no. 2 (August 1, 2016): 472–78. http://dx.doi.org/10.1152/jn.00321.2016.
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Interneuron-based cell transplantation is a powerful method to modify network function in a variety of neurological disorders, including epilepsy. Whether new interneurons integrate into native neural networks in a subtype-specific manner is not well understood, and the therapeutic mechanisms underlying interneuron-based cell therapy, including the role of synaptic inhibition, are debated. In this study, we tested subtype-specific integration of transplanted interneurons using acute cortical brain slices and visualized patch-clamp recordings to measure excitatory synaptic inputs, intrinsic properties, and inhibitory synaptic outputs. Fluorescently labeled progenitor cells from the embryonic medial ganglionic eminence (MGE) were used for transplantation. At 5 wk after transplantation, MGE-derived parvalbumin-positive (PV+) interneurons received excitatory synaptic inputs, exhibited mature interneuron firing properties, and made functional synaptic inhibitory connections to native pyramidal cells that were comparable to those of native PV+ interneurons. These findings demonstrate that MGE-derived PV+ interneurons functionally integrate into subtype-appropriate physiological niches within host networks following transplantation.
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Cruz-Santos, Maria, Lucia Fernandez Cardo, and Meng Li. "A Novel LHX6 Reporter Cell Line for Tracking Human iPSC-Derived Cortical Interneurons." Cells 11, no. 5 (March 1, 2022): 853. http://dx.doi.org/10.3390/cells11050853.
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GABAergic interneurons control the neural circuitry and network activity in the brain. The dysfunction of cortical interneurons, especially those derived from the medial ganglionic eminence, contributes to neurological disease states. Pluripotent stem cell-derived interneurons provide a powerful tool for understanding the etiology of neuropsychiatric disorders, as well as having the potential to be used as medicine in cell therapy for neurological conditions such as epilepsy. Although large numbers of interneuron progenitors can be readily induced in vitro, the generation of defined interneuron subtypes remains inefficient. Using CRISPR/Cas9-assisted homologous recombination in hPSCs, we inserted the coding sequence of mEmerald and mCherry fluorescence protein, respectively, downstream that of the LHX6, a gene required for, and a marker of medial ganglionic eminence (MGE)-derived cortical interneurons. Upon differentiation of the LHX6-mEmerald and LHX6-mCherry hPSCs towards the MGE fate, both reporters exhibited restricted expression in LHX6+ MGE derivatives of hPSCs. Moreover, the reporter expression responded to changes of interneuron inductive cues. Thus, the LHX6-reporter lines represent a valuable tool to identify molecules controlling human interneuron development and design better interneuron differentiation protocols as well as for studying risk genes associated with interneuronopathies.
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Nestor, Michael W., Samson Jacob, Bruce Sun, Deborah Prè, Andrew A. Sproul, Seong Im Hong, Chris Woodard, et al. "Characterization of a subpopulation of developing cortical interneurons from human iPSCs within serum-free embryoid bodies." American Journal of Physiology-Cell Physiology 308, no. 3 (February 1, 2015): C209—C219. http://dx.doi.org/10.1152/ajpcell.00263.2014.
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Production and isolation of forebrain interneuron progenitors are essential for understanding cortical development and developing cell-based therapies for developmental and neurodegenerative disorders. We demonstrate production of a population of putative calretinin-positive bipolar interneurons that express markers consistent with caudal ganglionic eminence identities. Using serum-free embryoid bodies (SFEBs) generated from human inducible pluripotent stem cells (iPSCs), we demonstrate that these interneuron progenitors exhibit morphological, immunocytochemical, and electrophysiological hallmarks of developing cortical interneurons. Finally, we develop a fluorescence-activated cell-sorting strategy to isolate interneuron progenitors from SFEBs to allow development of a purified population of these cells. Identification of this critical neuronal cell type within iPSC-derived SFEBs is an important and novel step in describing cortical development in this iPSC preparation.
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Yekhlef, Latefa, Gian Luca Breschi, Laura Lagostena, Giovanni Russo, and Stefano Taverna. "Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizurelike activity in mouse medial entorhinal cortex." Journal of Neurophysiology 113, no. 5 (March 1, 2015): 1616–30. http://dx.doi.org/10.1152/jn.00841.2014.
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GABAergic interneurons are thought to play a critical role in eliciting interictal spikes (IICs) and triggering ictal discharges in temporal lobe epilepsy, yet the contribution of different interneuronal subtypes to seizure initiation is still largely unknown. Here we took advantage of optogenetic techniques combined with patch-clamp and field recordings to selectively stimulate parvalbumin (PV)- or somatostatin (SOM)-positive interneurons expressing channelrhodopsin-2 (CHR-2) in layers II–III of adult mouse medial entorhinal cortical slices during extracellular perfusion with the proconvulsive compound 4-aminopyridine (4-AP, 100–200 μM). In control conditions, blue laser photostimulation selectively activated action potential firing in either PV or SOM interneurons and, in both cases, caused a robust GABAA-receptor-mediated inhibition in pyramidal cells (PCs). During perfusion with 4-AP, brief photostimuli (300 ms) activating either PV or SOM interneurons induced patterns of epileptiform activity that closely replicated spontaneously occurring IICs and tonic-clonic ictal discharges. Laser-induced synchronous firing in both interneuronal types elicited large compound GABAergic inhibitory postsynaptic currents (IPSCs) correlating with IICs and preictal spikes. In addition, spontaneous and laser-induced epileptic events were similarly initiated in concurrence with a large increase in extracellular potassium concentration. Finally, interneuron activation was unable to stop or significantly shorten the progression of seizurelike episodes. These results suggest that entorhinal PV and SOM interneurons are nearly equally effective in triggering interictal and ictal discharges that closely resemble human temporal lobe epileptic activity.
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Bryson, Alexander, Samuel F. Berkovic, Steven Petrou, and David B. Grayden. "State transitions through inhibitory interneurons in a cortical network model." PLOS Computational Biology 17, no. 10 (October 15, 2021): e1009521. http://dx.doi.org/10.1371/journal.pcbi.1009521.
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Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.
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De Gregorio, Roberto, Xiaoning Chen, Emilie I. Petit, Kostantin Dobrenis, and Ji Ying Sze. "Disruption of Transient SERT Expression in Thalamic Glutamatergic Neurons Alters Trajectory of Postnatal Interneuron Development in the Mouse Cortex." Cerebral Cortex 30, no. 3 (September 3, 2019): 1623–36. http://dx.doi.org/10.1093/cercor/bhz191.
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Abstract In mice, terminal differentiation of subpopulations of interneurons occurs in late postnatal stages, paralleling the emergence of the adult cortical architecture. Here, we investigated the effects of altered initial cortical architecture on later interneuron development. We identified that a class of somatostatin (SOM)-expressing GABAergic interneurons undergoes terminal differentiation between 2nd and 3rd postnatal week in the mouse somatosensory barrel cortex and upregulates Reelin expression during neurite outgrowth. Our previous work demonstrated that transient expression (E15-P10) of serotonin uptake transporter (SERT) in thalamocortical projection neurons regulates barrel elaboration during cortical map establishment. We show here that in thalamic neuron SERT knockout mice, these SOM-expressing interneurons develop at the right time, reach correct positions and express correct neurochemical markers, but only 70% of the neurons remain in the adult barrel cortex. Moreover, those neurons that remain display altered dendritic patterning. Our data indicate that a precise architecture at the cortical destination is not essential for specifying late-developing interneuron identities, their cortical deposition, and spatial organization, but dictates their number and dendritic structure ultimately integrated into the cortex. Our study illuminates how disruption of temporal-specific SERT function and related key regulators during cortical map establishment can alter interneuron development trajectory that persists to adult central nervous system.
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Favuzzi, Emilia, Rubén Deogracias, André Marques-Smith, Patricia Maeso, Julie Jezequel, David Exposito-Alonso, Maddalena Balia, et al. "Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits." Science 363, no. 6425 (January 24, 2019): 413–17. http://dx.doi.org/10.1126/science.aau8977.
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How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
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Taniguchi, Hiroki, Jiangteng Lu, and Z. Josh Huang. "The Spatial and Temporal Origin of Chandelier Cells in Mouse Neocortex." Science 339, no. 6115 (November 22, 2012): 70–74. http://dx.doi.org/10.1126/science.1227622.
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Diverse γ-aminobutyric acid–releasing interneurons regulate the functional organization of cortical circuits and derive from multiple embryonic sources. It remains unclear to what extent embryonic origin influences interneuron specification and cortical integration because of difficulties in tracking defined cell types. Here, we followed the developmental trajectory of chandelier cells (ChCs), the most distinct interneurons that innervate the axon initial segment of pyramidal neurons and control action potential initiation. ChCs mainly derive from the ventral germinal zone of the lateral ventricle during late gestation and require the homeodomain protein Nkx2.1 for their specification. They migrate with stereotyped routes and schedule and achieve specific laminar distribution in the cortex. The developmental specification of this bona fide interneuron type likely contributes to the assembly of a cortical circuit motif.
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Vaes, Josine E. G., Chantal M. Kosmeijer, Marthe Kaal, Rik van Vliet, Myrna J. V. Brandt, Manon J. N. L. Benders, and Cora H. Nijboer. "Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity." International Journal of Molecular Sciences 22, no. 1 (December 28, 2020): 211. http://dx.doi.org/10.3390/ijms22010211.
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Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.
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Marin, O. "CS06-01 - New insights into the cellular and molecular mechanisms underlying the etiology of schizophrenia." European Psychiatry 26, S2 (March 2011): 1786. http://dx.doi.org/10.1016/s0924-9338(11)73490-3.
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Growing evidence suggest that disruption of cortical interneuron function is common to several psychiatric conditions, such as schizophrenia. Cortical interneurons play major roles in the function of the cerebral cortex. Through mostly inhibitory mechanisms, interneurons regulate the activity of pyramidal cells, prevent hyperexcitability, and synchronize the rhythmic output of cortical activity. In particular, the function of some classes of interneurons has been shown to be crucial for the generation and maintenance of gamma rhythms, a pattern of brain waves that is associated with perception and memory.Work in my laboratory aims at elucidating the mechanisms controlling the development of cortical interneurons. We have recently found that several genes associated with schizophrenia, such as Nrg1 and ErbB4, control several aspects of the development of cortical interneurons. In this talk, I will summarize our current view on the biological mechanisms that may underlie the etiology of schizophrenia, linking susceptibility genes, cortical inhibitory function and brain development.
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Yang, Panzao, Joanne O. Davidson, Kelly Q. Zhou, Rani Wilson, Guido Wassink, Jaya D. Prasad, Laura Bennet, Alistair J. Gunn, and Justin M. Dean. "Therapeutic Hypothermia Attenuates Cortical Interneuron Loss after Cerebral Ischemia in Near-Term Fetal Sheep." International Journal of Molecular Sciences 24, no. 4 (February 12, 2023): 3706. http://dx.doi.org/10.3390/ijms24043706.
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Therapeutic hypothermia significantly improves outcomes after neonatal hypoxic-ischemic (HI) encephalopathy but is only partially protective. There is evidence that cortical inhibitory interneuron circuits are particularly vulnerable to HI and that loss of interneurons may be an important contributor to long-term neurological dysfunction in these infants. In the present study, we examined the hypothesis that the duration of hypothermia has differential effects on interneuron survival after HI. Near-term fetal sheep received sham ischemia or cerebral ischemia for 30 min, followed by cerebral hypothermia from 3 h after ischemia end and continued up to 48 h, 72 h, or 120 h recovery. Sheep were euthanized after 7 days for histology. Hypothermia up to 48 h recovery resulted in moderate neuroprotection of glutamate decarboxylase (GAD)+ and parvalbumin+ interneurons but did not improve survival of calbindin+ cells. Hypothermia up to 72 h recovery was associated with significantly increased survival of all three interneuron phenotypes compared with sham controls. By contrast, while hypothermia up to 120 h recovery did not further improve (or impair) GAD+ or parvalbumin+ neuronal survival compared with hypothermia up to 72 h, it was associated with decreased survival of calbindin+ interneurons. Finally, protection of parvalbumin+ and GAD+ interneurons, but not calbindin+ interneurons, with hypothermia was associated with improved recovery of electroencephalographic (EEG) power and frequency by day 7 after HI. The present study demonstrates differential effects of increasing the duration of hypothermia on interneuron survival after HI in near-term fetal sheep. These findings may contribute to the apparent preclinical and clinical lack of benefit of very prolonged hypothermia.
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Larimer, Phillip, Julien Spatazza, Michael P. Stryker, Arturo Alvarez-Buylla, and Andrea R. Hasenstaub. "Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment." Journal of Neurophysiology 118, no. 1 (July 1, 2017): 131–39. http://dx.doi.org/10.1152/jn.00096.2017.
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Interneuron precursors transplanted into visual cortex induce network plasticity during their heterochronic maturation. Such plasticity can have a significant impact on the function of the animal and is normally present only during a brief critical period in early postnatal development. Elucidating the synaptic and physiological properties of interneuron precursors as they mature is key to understanding how long-term circuit changes are induced by transplants. We studied the development of transplant-derived interneurons and compared it to endogenously developing interneurons (those that are born and develop in the same animal) at parallel developmental time points, using patch-clamp recordings in acute cortical slices. We found that transplant-derived interneurons develop into fast-spiking and non-fast-spiking neurons characteristic of the medial ganglionic eminence (MGE) lineage. Transplant-derived interneurons matured more rapidly than endogenously developing interneurons, as shown by more hyperpolarized membrane potentials, smaller input resistances, and narrower action potentials at a juvenile age. In addition, transplant-derived fast-spiking interneurons have more quickly saturating input-output relationships and lower maximal firing rates in adulthood, indicating a possible divergence in function. Transplant-derived interneurons both form inhibitory synapses onto host excitatory neurons and receive excitatory synapses from host pyramidal cells. Unitary connection properties are similar to those of host interneurons. These transplant-derived interneurons, however, were less densely functionally connected onto host pyramidal cells than were host interneurons and received fewer spontaneous excitatory inputs from host cells. These findings suggest that many physiological characteristics of interneurons are autonomously determined, while some factors impacting their circuit function may be influenced by the environment in which they develop. NEW & NOTEWORTHY Transplanting embryonic interneurons into older brains induces a period of plasticity in the recipient animal. We find that these interneurons develop typical fast-spiking and non-fast-spiking phenotypes by the end of adolescence. However, the input-output characteristics of transplant-derived neurons diverged from endogenously developing interneurons during adulthood, and they showed lower connection rates to local pyramidal cells at all time points. This suggests a unique and ongoing role of transplant-derived interneurons in host circuits, enabling interneuron transplant therapies.
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Hay, Y. Audrey, Jérémie Naudé, Philippe Faure, and Bertrand Lambolez. "Target Interneuron Preference in Thalamocortical Pathways Determines the Temporal Structure of Cortical Responses." Cerebral Cortex 29, no. 7 (July 27, 2018): 2815–31. http://dx.doi.org/10.1093/cercor/bhy148.
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Abstract Sensory processing relies on fast detection of changes in environment, as well as integration of contextual cues over time. The mechanisms by which local circuits of the cerebral cortex simultaneously perform these opposite processes remain obscure. Thalamic “specific” nuclei relay sensory information, whereas “nonspecific” nuclei convey information on the environmental and behavioral contexts. We expressed channelrhodopsin in the ventrobasal specific (sensory) or the rhomboid nonspecific (contextual) thalamic nuclei. By selectively activating each thalamic pathway, we found that nonspecific inputs powerfully activate adapting (slow-responding) interneurons but weakly connect fast-spiking interneurons, whereas specific inputs exhibit opposite interneuron preference. Specific inputs thereby induce rapid feedforward inhibition that limits response duration, whereas, in the same cortical area, nonspecific inputs elicit delayed feedforward inhibition that enables lasting recurrent excitation. Using a mean field model, we confirm that cortical response dynamics depends on the type of interneuron targeted by thalamocortical inputs and show that efficient recruitment of adapting interneurons prolongs the cortical response and allows the summation of sensory and contextual inputs. Hence, target choice between slow- and fast-responding inhibitory neurons endows cortical networks with a simple computational solution to perform both sensory detection and integration.
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Jones, Daniel L., MacKenzie A. Howard, Amelia Stanco, John L. R. Rubenstein, and Scott C. Baraban. "Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons." Journal of Neurophysiology 105, no. 5 (May 2011): 1984–91. http://dx.doi.org/10.1152/jn.00056.2011.
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Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice lacking Dlx1, early steps in interneuron development appear normal. Beginning at ∼1 mo of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in Dlx1−/− mice; this is accompanied by a reduction in GABAergic transmission and late-onset epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given that interneuron loss is relatively modest in Dlx1−/− mice. Here we report that voltage-clamp recordings of CA1 interneurons in hippocampal slices prepared from Dlx1−/− animals older than postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from younger animals (P9–12). Current-clamp recordings from interneurons at these early postnatal ages showed that interneurons in Dlx1−/− mutants were immature and more excitable, although membrane properties normalized by P30. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, caspase-3, and NeuN staining did not reveal frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1−/− mice. Delayed interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory reduction in the strength of excitatory transmission onto interneurons. This reduced excitation onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously observed in adult Dlx1−/− mice.
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Funk, Marzieh, Stefan Jaeger, Niklas Schülert, Cornelia Dorner-Ciossek, Holger Rosenbrock, and Volker Mack. "M181. DEVELOPMENTAL PROGRESSION OF INTERNEURON NETWORK DEFICITS IN A 15Q13.3 MICRODELETION MOUSE MODEL – A GLIMPSE ON ADOLESCENT PRIMING FOR SCHIZOPHRENIA?" Schizophrenia Bulletin 46, Supplement_1 (April 2020): S205. http://dx.doi.org/10.1093/schbul/sbaa030.493.
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Abstract Background Schizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthood Methods Immunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures. Results We initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenia-linked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice. Discussion In this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention.
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Ding, Chao, Vishalini Emmenegger, Kim Schaffrath, and Dirk Feldmeyer. "Layer-Specific Inhibitory Microcircuits of Layer 6 Interneurons in Rat Prefrontal Cortex." Cerebral Cortex 31, no. 1 (August 22, 2020): 32–47. http://dx.doi.org/10.1093/cercor/bhaa201.
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Abstract GABAergic interneurons in different cortical areas play important roles in diverse higher-order cognitive functions. The heterogeneity of interneurons is well characterized in different sensory cortices, in particular in primary somatosensory and visual cortex. However, the structural and functional properties of the medial prefrontal cortex (mPFC) interneurons have received less attention. In this study, a cluster analysis based on axonal projection patterns revealed four distinct clusters of L6 interneurons in rat mPFC: Cluster 1 interneurons showed axonal projections similar to Martinotti-like cells extending to layer 1, cluster 2 displayed translaminar projections mostly to layer 5, and cluster 3 interneuron axons were confined to the layer 6, whereas those of cluster 4 interneurons extend also into the white matter. Correlations were found between neuron location and axonal distribution in all clusters. Moreover, all cluster 1 L6 interneurons showed a monotonically adapting firing pattern with an initial high-frequency burst. All cluster 2 interneurons were fast-spiking, while neurons in cluster 3 and 4 showed heterogeneous firing patterns. Our data suggest that L6 interneurons that have distinct morphological and physiological characteristics are likely to innervate different targets in mPFC and thus play differential roles in the L6 microcircuitry and in mPFC-associated functions.
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Riedemann, Therese. "Diversity and Function of Somatostatin-Expressing Interneurons in the Cerebral Cortex." International Journal of Molecular Sciences 20, no. 12 (June 17, 2019): 2952. http://dx.doi.org/10.3390/ijms20122952.
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Inhibitory interneurons make up around 10–20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct and non-overlapping interneuron classes in the mouse neocortex, namely, parvalbumin-expressing, 5-HT3A receptor-expressing and somatostatin-expressing interneuron classes. Each class is, in turn, composed of a multitude of subclasses, resulting in a growing number of interneuron classes and subclasses. In this review, I will focus on the diversity of somatostatin-expressing interneurons (SOM+ INs) in the cerebral cortex and elucidate their function in cortical circuits. I will then discuss pathological consequences of a malfunctioning of SOM+ INs in neurological disorders such as major depressive disorder, and present future avenues in SOM research and brain pathologies.
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Guo, Teng, Guoping Liu, Heng Du, Yan Wen, Song Wei, Zhenmeiyu Li, Guangxu Tao, et al. "Dlx1/2 are Central and Essential Components in the Transcriptional Code for Generating Olfactory Bulb Interneurons." Cerebral Cortex 29, no. 11 (February 23, 2019): 4831–49. http://dx.doi.org/10.1093/cercor/bhz018.
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Abstract Generation of olfactory bulb (OB) interneurons requires neural stem/progenitor cell specification, proliferation, differentiation, and young interneuron migration and maturation. Here, we show that the homeobox transcription factors Dlx1/2 are central and essential components in the transcriptional code for generating OB interneurons. In Dlx1/2 constitutive null mutants, the differentiation of GSX2+ and ASCL1+ neural stem/progenitor cells in the dorsal lateral ganglionic eminence is blocked, resulting in a failure of OB interneuron generation. In Dlx1/2 conditional mutants (hGFAP-Cre; Dlx1/2F/− mice), GSX2+ and ASCL1+ neural stem/progenitor cells in the postnatal subventricular zone also fail to differentiate into OB interneurons. In contrast, overexpression of Dlx1&2 in embryonic mouse cortex led to ectopic production of OB-like interneurons that expressed Gad1, Sp8, Sp9, Arx, Pbx3, Etv1, Tshz1, and Prokr2. Pax6 mutants generate cortical ectopia with OB-like interneurons, but do not do so in compound Pax6; Dlx1/2 mutants. We propose that DLX1/2 promote OB interneuron development mainly through activating the expression of Sp8/9, which further promote Tshz1 and Prokr2 expression. Based on this study, in combination with earlier ones, we propose a transcriptional network for the process of OB interneuron development.
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Shen, Wei, Ru Ba, Yan Su, Yang Ni, Dongsheng Chen, Wei Xie, Samuel J. Pleasure, and Chunjie Zhao. "Foxg1 Regulates the Postnatal Development of Cortical Interneurons." Cerebral Cortex 29, no. 4 (April 18, 2018): 1547–60. http://dx.doi.org/10.1093/cercor/bhy051.
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AbstractAbnormalities in cortical interneurons are closely associated with neurological diseases. Most patients with Foxg1 syndrome experience seizures, suggesting a possible role of Foxg1 in the cortical interneuron development. Here, by conditional deletion of Foxg1, which was achieved by crossing Foxg1fl/fl with the Gad2-CreER line, we found the postnatal distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex were impaired. Further investigations revealed an enhanced dendritic complexity and decreased migration capacity of Foxg1-deficient interneurons, accompanied by remarkable downregulation of Dlx1 and CXCR4. Overexpression of Dlx1 or knock down its downstream Pak3 rescued the differentiation detects, demonstrated that Foxg1 functioned upstream of Dlx1-Pak3 signal pathway to regulate the postnatal development of cortical interneurons. Due to the imbalanced neural circuit, Foxg1 mutants showed increased seizure susceptibility. These findings will improve our understanding of the postnatal development of interneurons and help to elucidate the mechanisms underlying seizure in patients carrying Foxg1 mutations.
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Vasistha, Navneet A., Maria Pardo-Navarro, Janina Gasthaus, Dilys Weijers, Michaela K. Müller, Diego García-González, Susmita Malwade, et al. "Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner." Molecular Psychiatry 25, no. 10 (October 8, 2019): 2313–29. http://dx.doi.org/10.1038/s41380-019-0539-5.
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Abstract Severe infections during pregnancy are one of the major risk factors for cognitive impairment in the offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brains and how the impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e., proliferation of precursor cells, migration and positioning of neuroblasts, as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, and changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally derived insults have developmental stage-dependent effects, which contribute to the complex etiology of cognitive impairment in the affected offspring.
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Harward, Stephen C., and Derek G. Southwell. "Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy." Neurosurgical Focus 48, no. 4 (April 2020): E18. http://dx.doi.org/10.3171/2020.2.focus19955.
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Excitatory-inhibitory imbalance is central to epilepsy pathophysiology. Current surgical therapies for epilepsy, such as brain resection, laser ablation, and neurostimulation, target epileptic networks on macroscopic scales, without directly correcting the circuit-level aberrations responsible for seizures. The transplantation of inhibitory cortical interneurons represents a novel neurobiological method for modifying recipient neural circuits in a physiologically corrective manner. Transplanted immature interneurons have been found to disperse in the recipient brain parenchyma, where they develop elaborate structural morphologies, express histochemical markers of mature interneurons, and form functional inhibitory synapses onto recipient neurons. Transplanted interneurons also augment synaptic inhibition and alter recipient neural network synchrony, two physiological processes disrupted in various epilepsies. In rodent models of epilepsy, interneuron transplantation corrects recipient seizure phenotypes and associated behavioral abnormalities. As such, interneuron transplantation may represent a novel neurobiological approach to the surgical treatment of human epilepsy. Here, the authors describe the preclinical basis for applying interneuron transplantation to human epilepsy, discuss its potential clinical applications, and consider the translational hurdles to its development as a surgical therapy.
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Lee, L., L. Boorman, E. Glendenning, C. Christmas, P. Sharp, P. Redgrave, O. Shabir, E. Bracci, J. Berwick, and C. Howarth. "Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons." Cerebral Cortex 30, no. 4 (November 20, 2019): 2452–64. http://dx.doi.org/10.1093/cercor/bhz251.
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Abstract Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.
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Hu, Hang, and Ariel Agmon. "Properties of precise firing synchrony between synaptically coupled cortical interneurons depend on their mode of coupling." Journal of Neurophysiology 114, no. 1 (July 2015): 624–37. http://dx.doi.org/10.1152/jn.00304.2015.
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Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations.
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Seeher, Sandra, Bradley A. Carlson, Angela C. Miniard, Eva K. Wirth, Yassin Mahdi, Dolph L. Hatfield, Donna M. Driscoll, and Ulrich Schweizer. "Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice." Biochemical Journal 462, no. 1 (July 24, 2014): 67–75. http://dx.doi.org/10.1042/bj20140423.
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Selenoproteins contain the rare amino acid selenocysteine. Reduced selenium levels in the brain lead to a complex neurological phenotype affecting cortical and hippocampal GABAergic interneurons. Here we show that striatal interneuron density is reduced in mice with impaired selenoprotein expression.
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Mazza, Frank, Alexandre Guet-McCreight, Taufik A. Valiante, John D. Griffiths, and Etay Hay. "In-silico EEG biomarkers of reduced inhibition in human cortical microcircuits in depression." PLOS Computational Biology 19, no. 4 (April 10, 2023): e1010986. http://dx.doi.org/10.1371/journal.pcbi.1010986.
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Reduced cortical inhibition by somatostatin-expressing (SST) interneurons has been strongly associated with treatment-resistant depression. However, due to technical limitations it is impossible to establish experimentally in humans whether the effects of reduced SST interneuron inhibition on microcircuit activity have signatures detectable in clinically-relevant brain signals such as electroencephalography (EEG). To overcome these limitations, we simulated resting-state activity and EEG using detailed models of human cortical microcircuits with normal (healthy) or reduced SST interneuron inhibition (depression), and found that depression microcircuits exhibited increased theta, alpha and low beta power (4–16 Hz). The changes in depression involved a combination of an aperiodic broadband and periodic theta components. We then demonstrated the specificity of the EEG signatures of reduced SST interneuron inhibition by showing they were distinct from those corresponding to reduced parvalbumin-expressing (PV) interneuron inhibition. Our study thus links SST interneuron inhibition level to distinct features in EEG simulated from detailed human microcircuits, which can serve to better identify mechanistic subtypes of depression using EEG, and non-invasively monitor modulation of cortical inhibition.
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Cooke, James E., Martin C. Kahn, Edward O. Mann, Andrew J. King, Jan W. H. Schnupp, and Ben D. B. Willmore. "Contrast gain control occurs independently of both parvalbumin-positive interneuron activity and shunting inhibition in auditory cortex." Journal of Neurophysiology 123, no. 4 (April 1, 2020): 1536–51. http://dx.doi.org/10.1152/jn.00587.2019.
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We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.
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Litwin-Kumar, Ashok, Robert Rosenbaum, and Brent Doiron. "Inhibitory stabilization and visual coding in cortical circuits with multiple interneuron subtypes." Journal of Neurophysiology 115, no. 3 (March 1, 2016): 1399–409. http://dx.doi.org/10.1152/jn.00732.2015.
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Recent anatomical and functional characterization of cortical inhibitory interneurons has highlighted the diverse computations supported by different subtypes of interneurons. However, most theoretical models of cortex do not feature multiple classes of interneurons and rather assume a single homogeneous population. We study the dynamics of recurrent excitatory-inhibitory model cortical networks with parvalbumin (PV)-, somatostatin (SOM)-, and vasointestinal peptide-expressing (VIP) interneurons, with connectivity properties motivated by experimental recordings from mouse primary visual cortex. Our theory describes conditions under which the activity of such networks is stable and how perturbations of distinct neuronal subtypes recruit changes in activity through recurrent synaptic projections. We apply these conclusions to study the roles of each interneuron subtype in disinhibition, surround suppression, and subtractive or divisive modulation of orientation tuning curves. Our calculations and simulations determine the architectural and stimulus tuning conditions under which cortical activity consistent with experiment is possible. They also lead to novel predictions concerning connectivity and network dynamics that can be tested via optogenetic manipulations. Our work demonstrates that recurrent inhibitory dynamics must be taken into account to fully understand many properties of cortical dynamics observed in experiments.
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Xiang, Hui, Huan-Xin Chen, Xin-Xin Yu, Michael A. King, and Steven N. Roper. "Reduced Excitatory Drive in Interneurons in an Animal Model of Cortical Dysplasia." Journal of Neurophysiology 96, no. 2 (August 2006): 569–78. http://dx.doi.org/10.1152/jn.01133.2005.
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Cortical dysplasia (CD) is strongly associated with epilepsy. Enhanced excitability in dysplastic neuronal networks is believed to contribute to epileptogenesis, but the underlying mechanisms for the hyperexcitability are poorly understood. Cortical GABAergic interneurons provide the principal inhibition in the neuronal networks by forming inhibitory synapses on excitatory neurons. The aim of the present study was to determine if the function of interneurons in CD is compromised. In a rat model of CD, in utero irradiation, we studied spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) in cortical interneurons using whole cell recording techniques. Two types of interneurons, type I and type II, were identified based on their distinctive spike patterns and short-term synaptic plasticity. We found that the frequencies of sEPSCs and mEPSCs were significantly decreased in both types of interneurons in CD. However, the amplitude and kinetics of sEPSCs and mEPSCs were not different. Five-pulse, 20-Hz stimulation produced short-term depression in type I interneurons in both CD and control tissue. Type II interneurons showed a robust short-term facilitation in both CD and control tissue. Morphological analysis of biocytin-filled neurons revealed that dendritic trees of both types of interneurons were not altered in CD. Our results demonstrate that the excitatory drive, namely sEPSCs and mEPSCs, in two main types of interneuron is largely attenuated in CD, probably due to a reduction in the number of excitatory synapses on both types of interneurons in CD.
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Garrido, Jesús A., Niceto R. Luque, Silvia Tolu, and Egidio D’Angelo. "Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks." International Journal of Neural Systems 26, no. 05 (June 8, 2016): 1650020. http://dx.doi.org/10.1142/s0129065716500209.
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The majority of operations carried out by the brain require learning complex signal patterns for future recognition, retrieval and reuse. Although learning is thought to depend on multiple forms of long-term synaptic plasticity, the way this latter contributes to pattern recognition is still poorly understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses and at the inhibitory interneuron–interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity effectively distributed multiple patterns among available interneurons, thus allowing the simultaneous detection of multiple overlapping patterns. The addition of plasticity in intrinsic excitability made the system more robust allowing self-adjustment and rescaling in response to a broad range of input patterns. The combination of plasticity in lateral inhibitory connections and homeostatic mechanisms in the inhibitory interneurons optimized mutual information (MI) transfer. The storage of multiple complex patterns in plastic interneuron networks could be critical for the generation of sparse representations of information in excitatory neuron populations falling under their control.
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Murata, Yasunobu, and Matthew T. Colonnese. "GABAergic interneurons excite neonatal hippocampus in vivo." Science Advances 6, no. 24 (June 2020): eaba1430. http://dx.doi.org/10.1126/sciadv.aba1430.
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GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3 (P3) and are responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas visual cortex interneurons are already inhibitory by P3 and remain so throughout development. These regional and age-specific differences are the result of a change in chloride reversal potential, because direct activation of light-gated anion channels in glutamatergic neurons drives CA1 firing at P3, but silences it at P7 in CA1, and at all ages in visual cortex. This study in the intact brain reveals that GABAergic interneuron excitation is essential for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development.
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Keijser, Joram, and Henning Sprekeler. "Optimizing interneuron circuits for compartment-specific feedback inhibition." PLOS Computational Biology 18, no. 4 (April 28, 2022): e1009933. http://dx.doi.org/10.1371/journal.pcbi.1009933.
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Cortical circuits process information by rich recurrent interactions between excitatory neurons and inhibitory interneurons. One of the prime functions of interneurons is to stabilize the circuit by feedback inhibition, but the level of specificity on which inhibitory feedback operates is not fully resolved. We hypothesized that inhibitory circuits could enable separate feedback control loops for different synaptic input streams, by means of specific feedback inhibition to different neuronal compartments. To investigate this hypothesis, we adopted an optimization approach. Leveraging recent advances in training spiking network models, we optimized the connectivity and short-term plasticity of interneuron circuits for compartment-specific feedback inhibition onto pyramidal neurons. Over the course of the optimization, the interneurons diversified into two classes that resembled parvalbumin (PV) and somatostatin (SST) expressing interneurons. Using simulations and mathematical analyses, we show that the resulting circuit can be understood as a neural decoder that inverts the nonlinear biophysical computations performed within the pyramidal cells. Our model provides a proof of concept for studying structure-function relations in cortical circuits by a combination of gradient-based optimization and biologically plausible phenomenological models.
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Barthó, Peter, Hajime Hirase, Lenaïc Monconduit, Michael Zugaro, Kenneth D. Harris, and György Buzsáki. "Characterization of Neocortical Principal Cells and Interneurons by Network Interactions and Extracellular Features." Journal of Neurophysiology 92, no. 1 (July 2004): 600–608. http://dx.doi.org/10.1152/jn.01170.2003.
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Most neuronal interactions in the cortex occur within local circuits. Because principal cells and GABAergic interneurons contribute differently to cortical operations, their experimental identification and separation is of utmost important. We used 64-site two-dimensional silicon probes for high-density recording of local neurons in layer 5 of the somatosensory and prefrontal cortices of the rat. Multiple-site monitoring of units allowed for the determination of their two-dimensional spatial position in the brain. Of the ∼60,000 cell pairs recorded, 0.2% showed robust short-term interactions. Units with significant, short-latency (<3 ms) peaks following their action potentials in their cross-correlograms were characterized as putative excitatory (pyramidal) cells. Units with significant suppression of spiking of their partners were regarded as putative GABAergic interneurons. A portion of the putative interneurons was reciprocally connected with pyramidal cells. Neurons physiologically identified as inhibitory and excitatory cells were used as templates for classification of all recorded neurons. Of the several parameters tested, the duration of the unfiltered (1 Hz to 5 kHz) spike provided the most reliable clustering of the population. High-density parallel recordings of neuronal activity, determination of their physical location and their classification into pyramidal and interneuron classes provide the necessary tools for local circuit analysis.
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Jang, Hyun Jae, Hyowon Chung, James M. Rowland, Blake A. Richards, Michael M. Kohl, and Jeehyun Kwag. "Distinct roles of parvalbumin and somatostatin interneurons in gating the synchronization of spike times in the neocortex." Science Advances 6, no. 17 (April 2020): eaay5333. http://dx.doi.org/10.1126/sciadv.aay5333.
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Synchronization of precise spike times across multiple neurons carries information about sensory stimuli. Inhibitory interneurons are suggested to promote this synchronization, but it is unclear whether distinct interneuron subtypes provide different contributions. To test this, we examined single-unit recordings from barrel cortex in vivo and used optogenetics to determine the contribution of parvalbumin (PV)– and somatostatin (SST)–positive interneurons to the synchronization of spike times across cortical layers. We found that PV interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are low (<12 Hz), whereas SST interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are high (>12 Hz). Furthermore, using a computational model, we demonstrate that these effects can be explained by PV and SST interneurons having preferential contributions to feedforward and feedback inhibition, respectively. Our findings demonstrate that distinct subtypes of inhibitory interneurons have frequency-selective roles in the spatiotemporal synchronization of precise spike times.
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Kim, Jae-Yeon, and Mercedes F. Paredes. "Implications of Extended Inhibitory Neuron Development." International Journal of Molecular Sciences 22, no. 10 (May 12, 2021): 5113. http://dx.doi.org/10.3390/ijms22105113.
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A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.
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Gorelova, Natalia, Jeremy K. Seamans, and Charles R. Yang. "Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex." Journal of Neurophysiology 88, no. 6 (December 1, 2002): 3150–66. http://dx.doi.org/10.1152/jn.00335.2002.
Full textAbstract:
Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly and indirectly by way of its actions on local circuit GABAergic interneurons. DA modulation of interneuronal functions is implicated in the computational properties of prefrontal networks during cognitive processes and in schizophrenia. Morphologically and electrophysiologically distinct classes of putative GABAergic interneurons are found in layers II-V of rat prefrontal cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX-insensitive, reversible membrane depolarization, and increased the excitability of fast-spiking (FS) interneurons. The DA-induced membrane depolarization was reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2 receptor antagonist (−)sulpiride, D4 receptor antagonists U101958 or L-745870, α1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp analyses of the voltage-dependence of DA-sensitive currents, and the effects of changing [K+]O on reversal potentials of DA responses, revealed that DA suppressed a Cs+-sensitive inward rectifier K+ current and a resting leak K+ current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA on the leak current, but the DA effects on the inward rectifier K+ current were not mimicked by either agonist. In a subgroup of FS interneurons, the slowly inactivating membrane outward rectification evoked by depolarizing voltage steps was also attenuated by DA. Collectively, these data showed that DA depolarizes FS interneurons by suppressing a voltage-independent ‘leak’ K+ current (via D1/D5 receptor mechanism) and an inwardly rectifying K+ current (via unknown DA mechanisms). Additional suppression of a slowly inactivating K+ current led to increase in repetitive firing in response to depolarizing inputs. This D1-induced increase in interneuron excitability enhances GABAergic transmission to PFC pyramidal neurons and could represent a mechanism via which DA suppresses persistent firing of pyramidal neurons in vivo.
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Peng, Yangfan, Federico J. Barreda Tomas, Paul Pfeiffer, Moritz Drangmeister, Susanne Schreiber, Imre Vida, and Jörg R. P. Geiger. "Spatially structured inhibition defined by polarized parvalbumin interneuron axons promotes head direction tuning." Science Advances 7, no. 25 (June 2021): eabg4693. http://dx.doi.org/10.1126/sciadv.abg4693.
Full textAbstract:
In cortical microcircuits, it is generally assumed that fast-spiking parvalbumin interneurons mediate dense and nonselective inhibition. Some reports indicate sparse and structured inhibitory connectivity, but the computational relevance and the underlying spatial organization remain unresolved. In the rat superficial presubiculum, we find that inhibition by fast-spiking interneurons is organized in the form of a dominant super-reciprocal microcircuit motif where multiple pyramidal cells recurrently inhibit each other via a single interneuron. Multineuron recordings and subsequent 3D reconstructions and analysis further show that this nonrandom connectivity arises from an asymmetric, polarized morphology of fast-spiking interneuron axons, which individually cover different directions in the same volume. Network simulations assuming topographically organized input demonstrate that such polarized inhibition can improve head direction tuning of pyramidal cells in comparison to a “blanket of inhibition.” We propose that structured inhibition based on asymmetrical axons is an overarching spatial connectivity principle for tailored computation across brain regions.
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Woodruff, Alan R., and Pankaj Sah. "Inhibition and Synchronization of Basal Amygdala Principal Neuron Spiking by Parvalbumin-Positive Interneurons." Journal of Neurophysiology 98, no. 5 (November 2007): 2956–61. http://dx.doi.org/10.1152/jn.00739.2007.
Full textAbstract:
Using mice that express enhance green fluorescent protein (EGFP) under the control of the parvalbumin promoter, we made paired recordings from interneurons and principal neurons in the basal amygdala. In synaptically connected pairs, we show that single action potentials in a parvalbumin expressing interneuron can inhibit spiking in the synaptically connected principal neuron. When principal neurons were provided with suprathreshold oscillatory drive via a somatic patch pipette, action potentials in the interneuron inhibited spiking in principal neurons only when the interneuron spike occurred shortly before excitation reached threshold in the principal neuron. Moreover, after this spike inhibition, there was a rebound excitation in the principal neurons that was seen as an increased probability of firing on the cycle after inhibition. These results illustrate the major role of local inhibition in the basal amygdala. We propose that these interneurons in the basal amygdala provide a potent inhibition that acts to inhibit firing of principal neurons during cortically driven oscillations.
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Krishnan, Vijai, Lauren C. Wade-Kleyn, Ron R. Israeli, and Galit Pelled. "Peripheral Nerve Injury Induces Changes in the Activity of Inhibitory Interneurons as Visualized in Transgenic GAD1-GCaMP6s Rats." Biosensors 12, no. 6 (June 1, 2022): 383. http://dx.doi.org/10.3390/bios12060383.
Full textAbstract:
Peripheral nerve injury induces cortical remapping that can lead to sensory complications. There is evidence that inhibitory interneurons play a role in this process, but the exact mechanism remains unclear. Glutamate decarboxylase-1 (GAD1) is a protein expressed exclusively in inhibitory interneurons. Transgenic rats encoding GAD1–GCaMP were generated to visualize the activity in GAD1 neurons through genetically encoded calcium indicators (GCaMP6s) in the somatosensory cortex. Forepaw denervation was performed in adult rats, and fluorescent Ca2+ imaging on cortical slices was obtained. Local, intrahemispheric stimulation (cortical layers 2/3 and 5) induced a significantly higher fluorescence change of GAD1-expressing neurons, and a significantly higher number of neurons were responsive to stimulation in the denervated rats compared to control rats. However, remote, interhemispheric stimulation of the corpus callosum induced a significantly lower fluorescence change of GAD1-expressing neurons, and significantly fewer neurons were deemed responsive to stimulation within layer 5 in denervated rats compared to control rats. These results suggest that injury impacts interhemispheric communication, leading to an overall decrease in the activity of inhibitory interneurons in layer 5. Overall, our results provide direct evidence that inhibitory interneuron activity in the deprived S1 is altered after injury, a phenomenon likely to affect sensory processing.
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Kann, Oliver, Ismini E. Papageorgiou, and Andreas Draguhn. "Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks." Journal of Cerebral Blood Flow & Metabolism 34, no. 8 (June 4, 2014): 1270–82. http://dx.doi.org/10.1038/jcbfm.2014.104.
Full textAbstract:
Gamma oscillations (~30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency (‘fast-spiking’) and synchronize the activity of numerous pyramidal cells by rhythmic inhibition (‘clockwork’). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited (‘interneuron energy hypothesis’). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.
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Scheuer, Till, Elena auf dem Brinke, Sabine Grosser, Susanne A. Wolf, Daniele Mattei, Yuliya Sharkovska, Paula C. Barthel, et al. "Reduction of cortical parvalbumin expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition." Development, September 24, 2021. http://dx.doi.org/10.1242/dev.198390.
Full textAbstract:
The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the mechanisms underlying are not known. In a translational hyperoxia model, exposing mice pups at age P5 to 80% oxygen for 48 hours to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin expressing interneurons until adulthood. Developmental delay of cortical myelin was observed together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor being involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning, and attention. These results elucidate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.
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Gothner, Tina, Pedro J. Gonçalves, Maneesh Sahani, Jennifer F. Linden, and K. Jannis Hildebrandt. "Sustained Activation of PV+ Interneurons in Core Auditory Cortex Enables Robust Divisive Gain Control for Complex and Naturalistic Stimuli." Cerebral Cortex, December 10, 2020. http://dx.doi.org/10.1093/cercor/bhaa347.
Full textAbstract:
Abstract Sensory cortices must flexibly adapt their operations to internal states and external requirements. Sustained modulation of activity levels in different inhibitory interneuron populations may provide network-level mechanisms for adjustment of sensory cortical processing on behaviorally relevant timescales. However, understanding of the computational roles of inhibitory interneuron modulation has mostly been restricted to effects at short timescales, through the use of phasic optogenetic activation and transient stimuli. Here, we investigated how modulation of inhibitory interneurons affects cortical computation on longer timescales, by using sustained, network-wide optogenetic activation of parvalbumin-positive interneurons (the largest class of cortical inhibitory interneurons) to study modulation of auditory cortical responses to prolonged and naturalistic as well as transient stimuli. We found highly conserved spectral and temporal tuning in auditory cortical neurons, despite a profound reduction in overall network activity. This reduction was predominantly divisive, and consistent across simple, complex, and naturalistic stimuli. A recurrent network model with power-law input–output functions replicated our results. We conclude that modulation of parvalbumin-positive interneurons on timescales typical of sustained neuromodulation may provide a means for robust divisive gain control conserving stimulus representations.
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Bereshpolova, Yulia, Xiaojuan Hei, Jose-Manuel Alonso, and Harvey A. Swadlow. "Three rules govern thalamocortical connectivity of fast-spike inhibitory interneurons in the visual cortex." eLife 9 (December 8, 2020). http://dx.doi.org/10.7554/elife.60102.
Full textAbstract:
Some cortical neurons receive highly selective thalamocortical (TC) input, but others do not. Here, we examine connectivity of single thalamic neurons (lateral geniculate nucleus, LGN) onto putative fast-spike inhibitory interneurons in layer 4 of rabbit visual cortex. We show that three ‘rules’ regulate this connectivity. These rules concern: (1) the precision of retinotopic alignment, (2) the amplitude of the postsynaptic local field potential elicited near the interneuron by spikes of the LGN neuron, and (3) the interneuron’s response latency to strong, synchronous LGN input. We found that virtually all first-order fast-spike interneurons receive input from nearly all LGN axons that synapse nearby, regardless of their visual response properties. This was not the case for neighboring regular-spiking neurons. We conclude that profuse and highly promiscuous TC inputs to layer-4 fast-spike inhibitory interneurons generate response properties that are well-suited to mediate a fast, sensitive, and broadly tuned feed-forward inhibition of visual cortical excitatory neurons.
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Zechel, Sabrina, Yasushi Nakagawa, and Carlos F. Ibáñez. "Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons." eLife 5 (December 9, 2016). http://dx.doi.org/10.7554/elife.20770.
Full textAbstract:
Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.