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1
Pettem, Katherine L., Daisaku Yokomaku, Hideto Takahashi, Yuan Ge y Ann Marie Craig. "Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development". Journal of Cell Biology 200, n.º 3 (28 de enero de 2013): 321–36. http://dx.doi.org/10.1083/jcb.201206028.
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Rare variants in MDGAs (MAM domain–containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse–organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin–neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.
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Dejanovic, Borislav, Tiffany Wu, Ming-Chi Tsai, David Graykowski, Vineela D. Gandham, Christopher M. Rose, Corey E. Bakalarski et al. "Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models". Nature Aging 2, n.º 9 (20 de septiembre de 2022): 837–50. http://dx.doi.org/10.1038/s43587-022-00281-1.
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AbstractMicroglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
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Hu, Xiaoge, Jian-hong Luo y Junyu Xu. "The Interplay between Synaptic Activity and Neuroligin Function in the CNS". BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/498957.
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Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.
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Suckow, Arthur T., Davide Comoletti, Megan A. Waldrop, Merrie Mosedale, Sonya Egodage, Palmer Taylor y Steven D. Chessler. "Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic β-Cells and the Involvement of Neuroligin in Insulin Secretion". Endocrinology 149, n.º 12 (28 de agosto de 2008): 6006–17. http://dx.doi.org/10.1210/en.2008-0274.
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The composition of the β-cell exocytic machinery is very similar to that of neuronal synapses, and the developmental pathway of β-cells and neurons substantially overlap. β-Cells secrete γ-aminobutyric acid and express proteins that, in the brain, are specific markers of inhibitory synapses. Recently, neuronal coculture experiments have identified three families of synaptic cell-surface molecules (neurexins, neuroligins, and SynCAM) that drive synapse formation in vitro and that control the differentiation of nascent synapses into either excitatory or inhibitory fully mature nerve terminals. The inhibitory synapse-like character of the β-cells led us to hypothesize that members of these families of synapse-inducing adhesion molecules would be expressed in β-cells and that the pattern of expression would resemble that associated with neuronal inhibitory synaptogenesis. Here, we describe β-cell expression of the neuroligins, neurexins, and SynCAM, and show that neuroligin expression affects insulin secretion in INS-1 β-cells and rat islet cells. Our findings demonstrate that neuroligins and neurexins are expressed outside the central nervous system and help confer an inhibitory synaptic-like phenotype onto the β-cell surface. Analogous to their role in synaptic neurotransmission, neurexin-neuroligin interactions may play a role in the formation of the submembrane insulin secretory apparatus.
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Overstreet, Linda S. y Gary L. Westbrook. "Synapse Density Regulates Independence at Unitary Inhibitory Synapses". Journal of Neuroscience 23, n.º 7 (1 de abril de 2003): 2618–26. http://dx.doi.org/10.1523/jneurosci.23-07-02618.2003.
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Hines, Pamela J. "Inhibitory synapse specificity". Science 363, n.º 6425 (24 de enero de 2019): 360.6–361. http://dx.doi.org/10.1126/science.363.6425.360-f.
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Jasinska, Malgorzata, Ewa Siucinska, Ewa Jasek, Jan A. Litwin, Elzbieta Pyza y Malgorzata Kossut. "Effect of Associative Learning on Memory Spine Formation in Mouse Barrel Cortex". Neural Plasticity 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/9828517.
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Associative fear learning, in which stimulation of whiskers is paired with mild electric shock to the tail, modifies the barrel cortex, the functional representation of sensory receptors involved in the conditioning, by inducing formation of new inhibitory synapses on single-synapse spines of the cognate barrel hollows and thus producing double-synapse spines. In the barrel cortex of conditioned, pseudoconditioned, and untreated mice, we analyzed the number and morphological features of dendritic spines at various maturation and stability levels: sER-free spines, spines containing smooth endoplasmic reticulum (sER), and spines containing spine apparatus. Using stereological analysis of serial sections examined by transmission electron microscopy, we found that the density of double-synapse spines containing spine apparatus was significantly increased in the conditioned mice. Learning also induced enhancement of the postsynaptic density area of inhibitory synapses as well as increase in the number of polyribosomes in such spines. In single-synapse spines, the effects of conditioning were less pronounced and included increase in the number of polyribosomes in sER-free spines. The results suggest that fear learning differentially affects single- and double-synapse spines in the barrel cortex: it promotes maturation and stabilization of double-synapse spines, which might possibly contribute to permanent memory formation, and upregulates protein synthesis in single-synapse spines.
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Jasinska, Malgorzata, Ewa Siucinska, Stansislaw Glazewski, Elzbieta Pyza y And Kossut. "Characterization and plasticity of the double synapse spines in the barrel cortex of the mouse". Acta Neurobiologiae Experimentalis 66, n.º 2 (30 de junio de 2006): 99–104. http://dx.doi.org/10.55782/ane-2006-1595.
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The somatosensory barrel cortex of rodents and its afferent pathway from the facial vibrissae is a very useful model for studying neuronal plasticity. Dendritic spines are the most labile elements of synaptic circuitry and the most likely substrate of experience-dependent alterations in neuronal circuits in cerebral cortex. We characterized morphologically and numerically a specific population of spines, i.e. double synapse spines, which have two different inputs – one excitatory and the other inhibitory, in the B2 barrel of mouse somatosensory cortex. We also described changes in morphology of double synapse spines induced by classical conditioning in which stimulation of vibrissae was paired with a tail shock. The analysis was carried out by means of serial EM micrograph reconstruction. We showed that double spines account for about 10% of all analyzed spines. The morphology of a typical double synapse spine is similar to the morphology of single synapse spine and both consist of two parts – a large head and a narrow, long neck. Excitatory synapses are preferentially located on the head of double synapse spines and inhibitory synapses are usually located on the neck of these spines. The length of the double synapse spine neck decreases and the cross-section area of the spine neck increases significantly as a result of sensory conditioning. The correspondence should be addressed to E. Pyza, Email: pyza@zuk.iz.uj.edu.pl
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Wilson, Emily S. y Karen Newell-Litwa. "Stem cell models of human synapse development and degeneration". Molecular Biology of the Cell 29, n.º 24 (26 de noviembre de 2018): 2913–21. http://dx.doi.org/10.1091/mbc.e18-04-0222.
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Many brain disorders exhibit altered synapse formation in development or synapse loss with age. To understand the complexities of human synapse development and degeneration, scientists now engineer neurons and brain organoids from human-induced pluripotent stem cells (hIPSC). These hIPSC-derived brain models develop both excitatory and inhibitory synapses and functional synaptic activity. In this review, we address the ability of hIPSC-derived brain models to recapitulate synapse development and insights gained into the molecular mechanisms underlying synaptic alterations in neuronal disorders. We also discuss the potential for more accurate human brain models to advance our understanding of synapse development, degeneration, and therapeutic responses.
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Barreira da Silva, Rosa, Claudine Graf y Christian Münz. "Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells". Blood 118, n.º 25 (15 de diciembre de 2011): 6487–98. http://dx.doi.org/10.1182/blood-2011-07-366328.
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Abstract Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)–cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells.
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Treanor, Bebhinn, Peter M. P. Lanigan, Sunil Kumar, Chris Dunsby, Ian Munro, Egidijus Auksorius, Fiona J. Culley et al. "Microclusters of inhibitory killer immunoglobulin–like receptor signaling at natural killer cell immunological synapses". Journal of Cell Biology 174, n.º 1 (26 de junio de 2006): 153–61. http://dx.doi.org/10.1083/jcb.200601108.
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We report the supramolecular organization of killer Ig–like receptor (KIR) phosphorylation using a technique applicable to imaging phosphorylation of any green fluorescent protein–tagged receptor at an intercellular contact or immune synapse. Specifically, we use fluorescence lifetime imaging (FLIM) to report Förster resonance energy transfer (FRET) between GFP-tagged KIR2DL1 and a Cy3-tagged generic anti-phosphotyrosine monoclonal antibody. Visualization of KIR phosphorylation in natural killer (NK) cells contacting target cells expressing cognate major histocompatibility complex class I proteins revealed that inhibitory signaling is spatially restricted to the immune synapse. This explains how NK cells respond appropriately when simultaneously surveying susceptible and resistant target cells. More surprising, phosphorylated KIR was confined to microclusters within the aggregate of KIR, contrary to an expected homogeneous distribution of KIR signaling across the immune synapse. Also, yellow fluorescent protein–tagged Lck, a kinase important for KIR phosphorylation, accumulated in a multifocal distribution at inhibitory synapses. Spatial confinement of receptor phosphorylation within the immune synapse may be critical to how activating and inhibitory signals are integrated in NK cells.
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Takesian, Anne E., Vibhakar C. Kotak y Dan H. Sanes. "Age-dependent effect of hearing loss on cortical inhibitory synapse function". Journal of Neurophysiology 107, n.º 3 (febrero de 2012): 937–47. http://dx.doi.org/10.1152/jn.00515.2011.
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The developmental plasticity of excitatory synapses is well established, particularly as a function of age. If similar principles apply to inhibitory synapses, then we would expect manipulations during juvenile development to produce a greater effect and experience-dependent changes to persist into adulthood. In this study, we first characterized the maturation of cortical inhibitory synapse function from just before the onset of hearing through adulthood. We then examined the long-term effects of developmental conductive hearing loss (CHL). Whole cell recordings from gerbil thalamocortical brain slices revealed a significant decrease in the decay time of inhibitory currents during the first 3 mo of normal development. When assessed in adults, developmental CHL led to an enduring decrease of inhibitory synaptic strength, whereas the maturation of synaptic decay time was only delayed. Early CHL also depressed the maximum discharge rate of fast-spiking, but not low-threshold-spiking, inhibitory interneurons. We then asked whether adult onset CHL had a similar effect, but neither inhibitory current amplitude nor decay time was altered. Thus inhibitory synapse function displays a protracted development during which deficits can be induced by juvenile, but not adult, hearing loss. These long-lasting changes to inhibitory function may contribute to the auditory processing deficits associated with early hearing loss.
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Legendre, P. "The glycinergic inhibitory synapse". Cellular and Molecular Life Sciences 58, n.º 5 (mayo de 2001): 760–93. http://dx.doi.org/10.1007/pl00000899.
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Flores, Carmen E., Irina Nikonenko, Pablo Mendez, Jean-Marc Fritschy, Shiva K. Tyagarajan y Dominique Muller. "Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation". Proceedings of the National Academy of Sciences 112, n.º 1 (22 de diciembre de 2014): E65—E72. http://dx.doi.org/10.1073/pnas.1411170112.
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Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca2+/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.
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Holmes, William R. y William B. Levy. "Quantifying the Role of Inhibition in Associative Long-Term Potentiation in Dentate Granule Cells With Computational Models". Journal of Neurophysiology 78, n.º 1 (1 de julio de 1997): 103–16. http://dx.doi.org/10.1152/jn.1997.78.1.103.
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Holmes, William R. and William B. Levy. Quantifying the role of inhibition in associative long-term potentiation in dentate granule cells with computational models. J. Neurophysiol. 78: 103–116, 1997. In the dentate gyrus, coactivation of a mildly strong ipsilateral perforant path (pp) input with a weak contralateral pp input will not induce associative long-term potentiation in the weak input path unless both inputs project to the same part of the molecular layer. This “spatial convergence requirement” is thought to arise from either voltage attenuation between input locations or inhibition. Simulations with a detailed model of a dentate granule cell were performed to rule out voltage attenuation and to quantify the inhibition necessary to obtain the spatial convergence requirement. Strong lateral and weak medial or strong medial and weak lateral pp input were activated eight times at 400 Hz. Calcium current through N-methyl-d-aspartate receptor channels and subsequent changes in calcium concentration and the concentration of calmodulin bound with four calcium ions ([Cal-Ca4]) in the spine head were computed for a medial and a lateral pp synapse. To satisfy the spatial convergence requirement, peak [Cal-Ca4] had to be much larger in the strongly activated path synapse than in the weakly activated path synapse. With no inhibition in the model, differences in peak [Cal-Ca4] at the two synapses were small, ruling out voltage attenuation as the explanation of the spatial convergence requirement. However, with shunting inhibition, modeled by reducing membrane resistivity to 1,600 Ω cm2 in the distal two-thirds of the dendritic tree, peak [Cal-Ca4] was 3–5 times larger in the strongly activated path synapse than in the weakly activated path synapse. The magnitude of shunting inhibition was varied to determine the level that maximized this difference in peak [Cal-Ca4]. For strong lateral and weak medial pp input, the optimal level was one that prevented the cell from firing an action potential. For strong medial and weak lateral pp input, the optimal level was one at which the cell fired two action potentials. The distribution of shunting inhibition that best satisfied the spatial convergence requirement was inhibition on the distal two-thirds of the dendritic tree with or without inhibition at the soma, with inhibition stronger in the distal third than in the middle third. It was estimated that the number of inhibitory synapses involved in the shunting inhibition should be 25–50% of the number of excitatory synapses activated by the eight-pulse, 400-Hz tetanus. This number could be 20–50% of the total number of inhibitory synapses in the distal two-thirds of the dendritic tree. The addition of a single inhibitory synapse on a dendrite had a significant effect on peak spine head [Cal-Ca4] in nearby spines. Inhibitory synapses had to be activated four or more times at 100 Hz for effective shunting to take place, and the inhibition had to begin no later than2–5 ms after the first excitatory input. The results suggest that inhibition can isolate potentiated synapses to particular dendritic domains and that the location of activated inhibitory synapses may affect potentiation of individual synapses on individual dendrites.
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Ramaglia, Valeria, Mohit Dubey, M. Alfonso Malpede, Naomi Petersen, Sharon I. de Vries, Shanzeh M. Ahmed, Dennis S. W. Lee et al. "Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory". Acta Neuropathologica 142, n.º 4 (25 de junio de 2021): 643–67. http://dx.doi.org/10.1007/s00401-021-02338-8.
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AbstractThe complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by intrinsic changes and a reduced spike output. Finally, consistent with excitability deficits, we show that cuprizone-treated mice exhibit impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.
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Su, Jianmin, Jiang Chen, Kumiko Lippold, Aboozar Monavarfeshani, Gabriela Lizana Carrillo, Rachel Jenkins y Michael A. Fox. "Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex". Journal of Cell Biology 212, n.º 6 (14 de marzo de 2016): 721–36. http://dx.doi.org/10.1083/jcb.201509085.
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Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses.
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Woodin, Melanie A., Toshiro Hamakawa, Mayumi Takasaki, Ken Lukowiak y Naweed I. Syed. "Trophic Factor-Induced Plasticity of Synaptic Connections Between Identified Lymnaea Neurons". Learning & Memory 6, n.º 3 (1 de mayo de 1999): 307–16. http://dx.doi.org/10.1101/lm.6.3.307.
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Neurotrophic factors participate in both developmental and adult synaptic plasticity; however, the underlying mechanisms remain unknown. Using soma–soma synapses between the identified Lymnaea neurons, we demonstrate that the brain conditioned medium (CM)-derived trophic factors are required for the formation of excitatory but not the inhibitory synapse. Specifically, identified presynaptic [right pedal dorsal 1 (RPeD1) and visceral dorsal 4 (VD4)] and postsynaptic [visceral dorsal 2/3 (VD2/3) and left pedal dorsal 1 (LPeD1)] neurons were soma–soma paired either in the absence or presence of CM. We show that in defined medium (DM—does not contain extrinsic trophic factors), appropriate excitatory synapses failed to develop between RPeD1 and VD2/3. Instead, inappropriate inhibitory synapses formed between VD2/3 and RPeD1. Similarly, mutual inhibitory synapses developed between VD4 and LPeD1 in DM. These inhibitory synapses were termed novel because they do not exist in the intact brain. To test whether DM-induced, inappropriate inhibitory synapses could be corrected by the addition of CM, cells were first paired in DM for an initial period of 12 hr. DM was then replaced with CM, and simultaneous intracellular recordings were made from paired cells after 6–12 hr of CM substitution. Not only did CM induce the formation of appropriate excitatory synapses between both cell pairs, but it also reduced the incidence of inappropriate inhibitory synapse formation. The CM-induced plasticity of synaptic connections involved new protein synthesis and transcription and was mediated via receptor tyrosine kinases. Taken together, our data provide the first direct insight into the cellular mechanism underlying trophic factor-induced specificity and plasticity of synaptic connections between soma–soma paired Lymnaea neurons.
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Hoon, Mrinalini, Raunak Sinha, Haruhisa Okawa, Sachihiro C. Suzuki, Arlene A. Hirano, Nicholas Brecha, Fred Rieke y Rachel O. L. Wong. "Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells". Proceedings of the National Academy of Sciences 112, n.º 41 (29 de septiembre de 2015): 12840–45. http://dx.doi.org/10.1073/pnas.1510483112.
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Neuronal output is modulated by inhibition onto both dendrites and axons. It is unknown whether inhibitory synapses at these two cellular compartments of an individual neuron are regulated coordinately or separately during in vivo development. Because neurotransmission influences synapse maturation and circuit development, we determined how loss of inhibition affects the expression of diverse types of inhibitory receptors on the axon and dendrites of mouse retinal bipolar cells. We found that axonal GABA but not glycine receptor expression depends on neurotransmission. Importantly, axonal and dendritic GABAA receptors comprise distinct subunit compositions that are regulated differentially by GABA release: Axonal GABAA receptors are down-regulated but dendritic receptors are up-regulated in the absence of inhibition. The homeostatic increase in GABAA receptors on bipolar cell dendrites is pathway-specific: Cone but not rod bipolar cell dendrites maintain an up-regulation of receptors in the transmission deficient mutants. Furthermore, the bipolar cell GABAA receptor alterations are a consequence of impaired vesicular GABA release from amacrine but not horizontal interneurons. Thus, inhibitory neurotransmission regulates in vivo postsynaptic maturation of inhibitory synapses with contrasting modes of action specific to synapse type and location.
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ELMARIAH, SARINA B., ETHAN G. HUGHES, EUN JOO OH y RITA J. BALICE-GORDON. "Neurotrophin signaling among neurons and glia during formation of tripartite synapses". Neuron Glia Biology 1, n.º 4 (noviembre de 2004): 339–49. http://dx.doi.org/10.1017/s1740925x05000189.
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Synapse formation in the CNS is a complex process that involves the dynamic interplay of numerous signals exchanged between pre- and postsynaptic neurons as well as perisynaptic glia. Members of the neurotrophin family, which are widely expressed in the developing and mature CNS and are well-known for their roles in promoting neuronal survival and differentiation, have emerged as key synaptic modulators. However, the mechanisms by which neurotrophins modulate synapse formation and function are poorly understood. Here, we summarize our work on the role of neurotrophins in synaptogenesis in the CNS, in particular the role of these signaling molecules and their receptors, the Trks, in the development of excitatory and inhibitory hippocampal synapses. We discuss our results that demonstrate that postsynaptic TrkB signaling plays an important role in modulating the formation and maintenance of NMDA and GABAA receptor clusters at central synapses, and suggest that neurotrophin signaling coordinately modulates these receptors as part of mechanism that promotes the balance between excitation and inhibition in developing circuits. We also discuss our results that demonstrate that astrocytes promote the formation of GABAergic synapses in vitro by differentially regulating the development of inhibitory presynaptic terminals and postsynaptic GABAA receptor clusters, and suggest that glial modulation of inhibitory synaptogenesis is mediated by neurotrophin-dependent and -independent signaling. Together, these findings extend our understanding of how neuron–glia communication modulates synapse formation, maintenance and function, and set the stage for defining the cellular and molecular mechanisms by which neurotrophins and other cell–cell signals direct synaptogenesis in the developing brain.
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Jasinska, Malgorzata, Anna Grzegorczyk, Ewa Jasek, Jan Litwin, Malgorzata Kossut, Grazyna Barbacka-Surowiak y Elzbieta Pyza. "Daily rhythm of synapse turnover in mouse somatosensory cortex". Acta Neurobiologiae Experimentalis 74, n.º 1 (31 de marzo de 2014): 104–10. http://dx.doi.org/10.55782/ane-2014-1977.
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The whisker representations in the somatosensory barrel cortex of mice are modulated by sensory inputs associated with animal motor behavior which shows circadian rhythmicity. In a C57/BL mouse strain kept under a light/dark (LD 12:12) regime, we observed daily structural changes in the barrel cortex, correlated with the locomotor activity level. Stereological analysis of serial electron microscopic sections of the barrel cortex of mice sacrificed during their active or rest period, revealed an increase in the total numerical density of synapses and in the density of excitatory synapses located on dendritic spines during the rest, as well as an increase in the density of inhibitory synapses located on double-synapse spines during the active period. This is the first report demonstrating a daily rhythm in remodeling of the mammalian somatosensory cortex, manifested by changes in the density of synapses and dendritic spines. Moreover, we have found that the excitatory and inhibitory synapses are differently regulated during the day/night cycle.
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Ko, Jaewon, Gilberto J. Soler-Llavina, Marc V. Fuccillo, Robert C. Malenka y Thomas C. Südhof. "Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons". Journal of Cell Biology 194, n.º 2 (25 de julio de 2011): 323–34. http://dx.doi.org/10.1083/jcb.201101072.
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Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway.
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Woo, Jooyeon, Seok-Kyu Kwon, Jungyong Nam, Seungwon Choi, Hideto Takahashi, Dilja Krueger, Joohyun Park et al. "The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development". Journal of Cell Biology 201, n.º 6 (10 de junio de 2013): 929–44. http://dx.doi.org/10.1083/jcb.201209132.
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Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor– and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.
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Levinson, Joshua N. y Alaa El-Husseini. "New Players Tip the Scales in the Balance between Excitatory and Inhibitory Synapses". Molecular Pain 1 (1 de enero de 2005): 1744–8069. http://dx.doi.org/10.1186/1744-8069-1-12.
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Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.
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Thakar, Sonal, Liqing Wang, Ting Yu, Mao Ye, Keisuke Onishi, John Scott, Jiaxuan Qi et al. "Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation". Proceedings of the National Academy of Sciences 114, n.º 4 (5 de enero de 2017): E610—E618. http://dx.doi.org/10.1073/pnas.1612062114.
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The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.
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Lee, Sang-Eun, Yoonju Kim, Jeong-Kyu Han, Hoyong Park, Unghwi Lee, Myeongsu Na, Soomin Jeong, ChiHye Chung, Gianluca Cestra y Sunghoe Chang. "nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology". Proceedings of the National Academy of Sciences 113, n.º 24 (25 de mayo de 2016): 6749–54. http://dx.doi.org/10.1073/pnas.1600944113.
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Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott–Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder.
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Ojima, Daiki, Yoko Tominaga, Takashi Kubota, Atsushi Tada, Hiroo Takahashi, Yasushi Kishimoto, Takashi Tominaga y Tohru Yamamoto. "Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of d-Cycloserine". International Journal of Molecular Sciences 25, n.º 17 (6 de septiembre de 2024): 9674. http://dx.doi.org/10.3390/ijms25179674.
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The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory–inhibitory (E/I) balance. Mdga1−/− mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/− mice. As observed in Mdga1−/− mice, Mdga1+/− mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of d-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/− mice, while having no such effect on Mdga1−/− mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.
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Apollonio, Benedetta, Mariam Fanous, Mohamed-Reda Benmebarek, Stephen Devereux, Patrick Hagner, Michael Pourdehnad, Anita K. Gandhi, Piers E. Patten y Alan G. Ramsay. "CC-122 Repairs T Cell Activation in Chronic Lymphocytic Leukemia That Results in a Concomitant Increase in PD-1:PD-L1 and CTLA-4 Immune Checkpoint Expression at the Immunological Synapse". Blood 126, n.º 23 (3 de diciembre de 2015): 1738. http://dx.doi.org/10.1182/blood.v126.23.1738.1738.
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Abstract Immunomodulatory drugs (IMiDs®) such as lenalidomide and immune checkpoint blockade (ICB) antibodies can enhance autologous anti-tumor T cell immunity and have the potential to elicit durable control of disease in B cell malignancies. These immunotherapies are likely to be most effective when employed in treatment combinations. Thus, the goal of pre-clinical research should be to reveal mechanisms of action (MOA) in the tumor microenvironment (TME) and identify biomarkers to guide development of combination therapy for patients. CC-122 is a novel first-in-class pleiotropic pathway modifier (PPM®) that has potent anti-proliferative, anti-angiogenic and immunomodulatory activities and is currently in Phase I clinical trials for lymphoma and chronic lymphocytic leukemia (CLL). Here, we have utilized the immunological synapse bioassay to examine T cell interactions with CLL tumor cells (modeling anti-tumor T cell responses in the TME) following CC-122 treatment and measure the expression of co-signaling complexes at the synapse. Conjugation assays and confocal imaging were used to visualize intercellular conjugate interactions and F-actin polymerization at the immune synapse between CD4+ and CD8+ T cells and autologous CLL tumor cells pulsed with superantigen (acting as antigen-presenting cells, APCs). Peripheral blood was obtained from treatment naive CLL patients (n=40) representative of disease heterogeneity. Treatment of both purified CLL cells and CD4+ or CD8+ T cells with CC-122 (0.01 - 1 μM for 24h) dramatically enhanced the number of T cells recognizing tumor cells (% conjugation) and increased the formation of F-actin immune synapses (area, μm2) compared to vehicle treated cells (P<.01). Notably, CC-122 treatment induced T cells to engage in multiple tumor cell synapse interactions that were more pronounced in restored CD8+ T cell lytic synapses. This immunomodulatory activity was detected across all CLL patient samples and drug concentrations tested. In addition, synapse strength as measured by total fluorescence intensity of F-actin per T cell:APC conjugate increased significantly with CC-122 (P<.01). A critical MOA of lenalidomide is activation of T cell immune synapse signaling. Here, our comparative studies revealed that CC-122 (0.1 - 1 μM) significantly enhanced autologous T cell synapse activity in CLL by 4 - 5 fold versus vehicle (P<.01), whereas lenalidomide (1 μM) enhanced activity by 3 fold vs vehicle. Moreover, CC-122 treatment resulted in increased expression and polarization of tyrosine-phosphorylated proteins at T cell synapses compared to lenalidomide and vehicle treatment (P<.01). This data provides evidence that CC-122 induces functional T cell synapses that control the assembly of signaling complexes between the T cell receptor (TCR) and the F-actin cytoskeletal layer. Following T cell recognition of APCs, co-signaling receptors co-localize at the immune synapse where they synergize with TCR signaling to promote (co-stimulatory receptors) or inhibit (co-inhibitory/'immune checkpoint' receptors) T cell activation. Quantitative image analysis studies revealed that restoration of T cell synapse activity with CC-122 was accompanied by an increased recruitment of inducible co-stimulator (ICOS) to the synapse that was dose-dependent (P<.01). CC-122 treatment also increased polarized expression of CTLA-4 and PD-1 immune checkpoint proteins at the synapse with PD-L1+ tumor cells. The observed up-regulation of co-inhibitory receptors led to combining CC-122 with anti-PD-L1, anti-PD-1 or anti-CTLA-4 blocking antibodies. Results show that these treatment combinations increased T cell synapse activity compared to using these immunotherapies alone (P<.01). In conclusion, our results demonstrate for the first time that CC-122 can activate T cell immune synapse signaling against autologous CLL tumor cells and this immunomodulatory capability is more potent than lenalidomide. We further show that CC-122 activation of T cells is associated with enhanced expression of the co-stimulatory receptor ICOS and co-inhibitory checkpoints CTLA-4 and PD-1 at the synapse site. Importantly, our pre-clinical data demonstrates that this regulatory feedback inhibition can be exploited by the addition of anti-PD-L1, anti-PD-1 or anti-CTLA-4 ICB to CC-122 to more optimally stimulate T cell activity against immunosuppressive tumor cells. Disclosures Hagner: Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment. Gandhi:Celgene: Employment, Equity Ownership. Ramsay:MedImmune: Research Funding; Celgene: Research Funding.
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Ishibashi, Masaru, Kiyoshi Egawa y Atsuo Fukuda. "Diverse Actions of Astrocytes in GABAergic Signaling". International Journal of Molecular Sciences 20, n.º 12 (18 de junio de 2019): 2964. http://dx.doi.org/10.3390/ijms20122964.
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An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the “tripartite” synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.
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Zhang, Lulu, Yongzhi Zhang, Furong Liu, Qingyuan Chen, Yangbo Lian y Quanlong Ma. "On-Chip Photonic Synapses with All-Optical Memory and Neural Network Computation". Micromachines 14, n.º 1 (27 de diciembre de 2022): 74. http://dx.doi.org/10.3390/mi14010074.
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Inspired by the human brain, neural network computing was expected to break the bottleneck of traditional computing, but the integrated design still faces great challenges. Here, a readily integrated membrane-system photonic synapse was demonstrated. By pre-pulse training at 1064 nm (cutoff wavelength), the photonic synapse can be regulated both excitatory and inhibitory at tunable wavelengths (1200–2000 nm). Furthermore, more weights and memory functions were shown through the photonic synapse integrated network. Additionally, the digital recognition function of the single-layer perceptron neural network constructed by photonic synapses has been successfully demonstrated. Most of the biological synaptic functions were realized by the photonic synaptic network, and it had the advantages of compact structure, scalable, adjustable wavelength, and so on, which opens up a new idea for the study of the neural synaptic network.
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Wichmann, Carolin y Thomas Kuner. "Heterogeneity of glutamatergic synapses: cellular mechanisms and network consequences". Physiological Reviews 102, n.º 1 (1 de enero de 2022): 269–318. http://dx.doi.org/10.1152/physrev.00039.2020.
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Chemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons. They represent the smallest “computational” unit of the brain and are typically divided into excitatory and inhibitory as well as modulatory categories. These categories are subdivided into diverse types, each representing a different structure-function repertoire that in turn are thought to endow neuronal networks with distinct computational properties. The diversity of structure and function found among a given category of synapses is referred to as heterogeneity. The main building blocks for this heterogeneity are synaptic vesicles, the active zone, the synaptic cleft, the postsynaptic density, and glial processes associated with the synapse. Each of these five structural modules entails a distinct repertoire of functions, and their combination specifies the range of functional heterogeneity at mammalian excitatory synapses, which are the focus of this review. We describe synapse heterogeneity that is manifested on different levels of complexity ranging from the cellular morphology of the pre- and postsynaptic cells toward the expression of different protein isoforms at individual release sites. We attempt to define the range of structural building blocks that are used to vary the basic functional repertoire of excitatory synaptic contacts and discuss sources and general mechanisms of synapse heterogeneity. Finally, we explore the possible impact of synapse heterogeneity on neuronal network function.
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Kuljis, Dika A., Kristina D. Micheva, Ajit Ray, Waja Wegner, Ryan Bowman, Daniel V. Madison, Katrin I. Willig y Alison L. Barth. "Gephyrin-Lacking PV Synapses on Neocortical Pyramidal Neurons". International Journal of Molecular Sciences 22, n.º 18 (17 de septiembre de 2021): 10032. http://dx.doi.org/10.3390/ijms221810032.
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Gephyrin has long been thought of as a master regulator for inhibitory synapses, acting as a scaffold to organize γ-aminobutyric acid type A receptors (GABAARs) at the post-synaptic density. Accordingly, gephyrin immunostaining has been used as an indicator of inhibitory synapses; despite this, the pan-synaptic localization of gephyrin to specific classes of inhibitory synapses has not been demonstrated. Genetically encoded fibronectin intrabodies generated with mRNA display (FingRs) against gephyrin (Gephyrin.FingR) reliably label endogenous gephyrin, and can be tagged with fluorophores for comprehensive synaptic quantitation and monitoring. Here we investigated input- and target-specific localization of gephyrin at a defined class of inhibitory synapse, using Gephyrin.FingR proteins tagged with EGFP in brain tissue from transgenic mice. Parvalbumin-expressing (PV) neuron presynaptic boutons labeled using Cre- dependent synaptophysin-tdTomato were aligned with postsynaptic Gephyrin.FingR puncta. We discovered that more than one-third of PV boutons adjacent to neocortical pyramidal (Pyr) cell somas lack postsynaptic gephyrin labeling. This finding was confirmed using correlative fluorescence and electron microscopy. Our findings suggest some inhibitory synapses may lack gephyrin. Gephyrin-lacking synapses may play an important role in dynamically regulating cell activity under different physiological conditions.
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Gonzalez-Burgos, Guillermo, Diana C. Rotaru, Aleksey V. Zaitsev, Nadezhda V. Povysheva y David A. Lewis. "GABA Transporter GAT1 Prevents Spillover at Proximal and Distal GABA Synapses Onto Primate Prefrontal Cortex Neurons". Journal of Neurophysiology 101, n.º 2 (febrero de 2009): 533–47. http://dx.doi.org/10.1152/jn.91161.2008.
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The plasma membrane GABA transporter GAT1 is thought to mediate uptake of synaptically released GABA. In the primate dorsolateral prefrontal cortex (DLPFC), GAT1 expression changes significantly during development and in schizophrenia. The consequences of such changes, however, are not well understood because GAT1's role has not been investigated in primate neocortical circuits. We thus studied the effects of the GAT1 blocker 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy] ethyl]- 3-pyridinecarboxylic acid hydrochloride (NO711) on GABA transmission onto pyramidal neurons of monkey DLPFC. As in rat cortex, in monkey DLPFC NO711 did not substantially alter miniature GABA transmission, suggesting that GAT1 does not regulate single-synapse transmission. In rat cortical circuits, between-synapse GABA spillover produced by NO711 clearly prolongs the inhibitory postsynaptic currents, but whether NO711 also prolongs the inhibitory postsynaptic potentials (IPSPs) is unclear. Moreover, whether spillover differentially affects perisomatic versus dendritic inputs has not been examined. Here we found that NO711 prolonged the GABAA receptor-mediated IPSPs (GABAAR-IPSPs) evoked by stimulating perisomatic synapses. Dendritic, but not perisomatic, synapse stimulation often elicited a postsynaptic GABAB receptor-mediated IPSP that was enhanced by NO711. Blocking GABAB receptors revealed that NO711 prolonged the GABAAR-IPSPs evoked by stimulation of dendrite-targeting inputs. We conclude that a major functional role for GAT1 in primate cortical circuits is to prevent the effects of GABA spillover when multiple synapses are simultaneously active. Furthermore, we report that, at least in monkey DLPFC, GAT1 similarly restricts GABA spillover onto perisomatic or dendritic inputs, critically controlling the spatiotemporal specificity of inhibitory inputs onto proximal or distal compartments of the pyramidal cell membrane.
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Harrison, John M., Richard G. Allen, Michael J. Pellegrino, John T. Williams y Olivier J. Manzoni. "Chronic Morphine Treatment Alters Endogenous Opioid Control of Hippocampal Mossy Fiber Synaptic Transmission". Journal of Neurophysiology 87, n.º 5 (1 de mayo de 2002): 2464–70. http://dx.doi.org/10.1152/jn.2002.87.5.2464.
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Synaptic adaptations are thought to be an important component of the consequences of drug abuse. One such adaptation is an up-regulation of adenylyl cyclase that has been shown to increase transmitter release at several inhibitory synapses. In this study the effects of chronic morphine treatment were studied on mossy fiber synapses in the guinea pig hippocampus using extracellular field potential recordings. This opioid-sensitive synapse was chosen because of the known role of the adenylyl cyclase cascade in the regulation of glutamate release. Long-term potentiation (LTP) at the mossy fiber synapse was enhanced after chronic morphine treatment. In control animals, opioid antagonists increased LTP but had no effect in morphine-treated guinea pigs. In contrast, the long-lasting depression of transmission induced by a mGluR agonist and CA1 LTP were not altered. Chronic morphine treatment neither caused tolerance to μ- and κ-receptor–mediated inhibition at the mossy fiber synapse nor modified total hippocampal dynorphin levels. The results suggest that the phasic inhibition of glutamate transmission mediated by endogenous opioids is reduced after chronic exposure to morphine.
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Qian, N. y T. J. Sejnowski. "When is an inhibitory synapse effective?" Proceedings of the National Academy of Sciences 87, n.º 20 (1 de octubre de 1990): 8145–49. http://dx.doi.org/10.1073/pnas.87.20.8145.
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PEREIRA, T., M. S. BAPTISTA, J. KURTHS y M. B. REYES. "ONSET OF PHASE SYNCHRONIZATION IN NEURONS WITH CHEMICAL SYNAPSE". International Journal of Bifurcation and Chaos 17, n.º 10 (octubre de 2007): 3545–49. http://dx.doi.org/10.1142/s0218127407019342.
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We study the onset of synchronous states in realistic chaotic neurons coupled by mutually inhibitory chemical synapses. For the realistic parameters, namely the synaptic strength and the intrinsic current, this synapse introduces noncoherences in the neuronal dynamics, yet allowing for chaotic phase synchronization in a large range of parameters. As we increase the synaptic strength, the neurons reach a periodic state, and no chaotic complete synchronization is found.
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Grimes, William N., Jun Zhang, Hua Tian, Cole W. Graydon, Mrinalini Hoon, Fred Rieke y Jeffrey S. Diamond. "Complex inhibitory microcircuitry regulates retinal signaling near visual threshold". Journal of Neurophysiology 114, n.º 1 (julio de 2015): 341–53. http://dx.doi.org/10.1152/jn.00017.2015.
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Neuronal microcircuits, small, localized signaling motifs involving two or more neurons, underlie signal processing and computation in the brain. Compartmentalized signaling within a neuron may enable it to participate in multiple, independent microcircuits. Each A17 amacrine cell in the mammalian retina contains within its dendrites hundreds of synaptic feedback microcircuits that operate independently to modulate feedforward signaling in the inner retina. Each of these microcircuits comprises a small (<1 μm) synaptic varicosity that typically receives one excitatory synapse from a presynaptic rod bipolar cell (RBC) and returns two reciprocal inhibitory synapses back onto the same RBC terminal. Feedback inhibition from the A17 sculpts the feedforward signal from the RBC to the AII, a critical component of the circuitry mediating night vision. Here, we show that the two inhibitory synapses from the A17 to the RBC express kinetically distinct populations of GABA receptors: rapidly activating GABAARs are enriched at one synapse while more slowly activating GABACRs are enriched at the other. Anatomical and electrophysiological data suggest that macromolecular complexes of voltage-gated (Cav) channels and Ca2+-activated K+ channels help to regulate GABA release from A17 varicosities and limit GABACR activation under certain conditions. Finally, we find that selective elimination of A17-mediated feedback inhibition reduces the signal to noise ratio of responses to dim flashes recorded in the feedforward pathway (i.e., the AII amacrine cell). We conclude that A17-mediated feedback inhibition improves the signal to noise ratio of RBC-AII transmission near visual threshold, thereby improving visual sensitivity at night.
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Zhao, Qing-Tai, Fengben Xi, Yi Han, Andreas Grenmyr, Jin Hee Bae y Detlev Gruetzmacher. "Ferroelectric Devices for Neuromorphic Computing". ECS Meeting Abstracts MA2022-02, n.º 32 (9 de octubre de 2022): 1183. http://dx.doi.org/10.1149/ma2022-02321183mtgabs.
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Neuromorphic computing inspired by the neural network systems of the human brain enables energy efficient computing for big-data processing. A neural network is formed by thousands or even millions of neurons which are connected by even a higher number of synapses. Neurons communicate with each other through the connected synapses. The main responsibility of synapses is to transfer information from the pre-synaptic to the postsynaptic neurons. Synapses can memorize and process the information simultaneously. The plasticity of a synapse to strengthen or weaken their activity over time make it capable of learning and computing. Thus, artificial synapses which can emulate functionalities and the plasticity of bio-synapses form the backbones of neuromorphic computing. Alternative artificial synapses have been successfully demonstrated. The classical two-terminal memristor devices, like resistive random access memory (ReRAM), phase change memory (PCM) and ferroelectric tunnel junctions (FTJs) with one terminal connected to the pre-synaptic neuron and another connected with the post-synaptic neuron, own advantages of simple structure, easy processing with high density, and capability of integration with CMOS. However, signal processing and learning cannot be performed simultaneously in 2-terminal devices, thus limiting their synaptic functionalities. Ferroelectric field effect transistors (FeFET) which uses ferroelectric as the gate oxide are the most interesting three-terminal artificial synapse devices, in which the gate or the source is connected to the pre-synaptic neuron while the drain is used for the terminal of the post-synaptic neuron , thus can perform signal transmission and learning simultaneously. However, traps at the channel interface can degrade the device performance causing low endurance. Focuses of those abovementioned devices have been mainly put on the homosynaptic plasticity, which is input specific, meaning that the plasticity occurs only at the synapse with a pre-synaptic activation . The homosynaptic plasticity has a drawback of positive feedback loop: when a synapse is potentiated, the probability of the synapse to be further potentiated is increased. Similarly, when a synapse is depressed the probability of the synapse of being further depressed is higher. Therefore, synaptic weights tend to be either strengthened to the maximum value or weakened to zero, causing the system to be unstable. In contrast, heterosynaptic plasticity can be induced at any synapse at the same time after episodes of strong postsynaptic activity, avoiding the positive feedback problem and stabilize the activity of the post-synaptic neuron. To address the above challenges we proposed a very simple 4-terminal synapse structure based on gated Schottky diodes on silicon (FEMOD) with a ferroelectric layer. The conductance of the Schottky diode is modulated by the polarization of the ferroelectric layer. With this simple synapse structure we can achieve multiple hetero-synaptic functions, including excitatory/ inhibitory post-synaptic current (EPSC/IPSC), paired-pulse facilitation/depression (PPF/PPD), long-term potentiation/depression (LTP/LTD), as well as biological neuron-like spike-timing-dependent plasticity (STDP) characteristics. The modulatory synapse can modify the weight of another synapse with a very low voltage. Furthermore, logic gates, like AND and NAND which are highly desired for in-memory computing can be realized with such simple structure. Figure 1
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Fenyves, Bánk G., Gábor S. Szilágyi, Zsolt Vassy, Csaba Sőti y Peter Csermely. "Synaptic polarity and sign-balance prediction using gene expression data in the Caenorhabditis elegans chemical synapse neuronal connectome network". PLOS Computational Biology 16, n.º 12 (21 de diciembre de 2020): e1007974. http://dx.doi.org/10.1371/journal.pcbi.1007974.
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Graph theoretical analyses of nervous systems usually omit the aspect of connection polarity, due to data insufficiency. The chemical synapse network of Caenorhabditis elegans is a well-reconstructed directed network, but the signs of its connections are yet to be elucidated. Here, we present the gene expression-based sign prediction of the ionotropic chemical synapse connectome of C. elegans (3,638 connections and 20,589 synapses total), incorporating available presynaptic neurotransmitter and postsynaptic receptor gene expression data for three major neurotransmitter systems. We made predictions for more than two-thirds of these chemical synapses and observed an excitatory-inhibitory (E:I) ratio close to 4:1 which was found similar to that observed in many real-world networks. Our open source tool (http://EleganSign.linkgroup.hu) is simple but efficient in predicting polarities by integrating neuronal connectome and gene expression data.
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Lee, Seong-Eun y Gum Hwa Lee. "Reelin Affects Signaling Pathways of a Group of Inhibitory Neurons and the Development of Inhibitory Synapses in Primary Neurons". International Journal of Molecular Sciences 22, n.º 14 (13 de julio de 2021): 7510. http://dx.doi.org/10.3390/ijms22147510.
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Reelin is a secretory protein involved in a variety of processes in forebrain development and function, including neuronal migration, dendrite growth, spine formation, and synaptic plasticity. Most of the function of Reelin is focused on excitatory neurons; however, little is known about its effects on inhibitory neurons and inhibitory synapses. In this study, we investigated the phosphatidylinositol 3-kinase/Akt pathway of Reelin in primary cortical and hippocampal neurons. Individual neurons were visualized using immunofluorescence to distinguish inhibitory neurons from excitatory neurons. Reelin-rich protein supplementation significantly induced the phosphorylation of Akt and ribosomal S6 protein in excitatory neurons, but not in most inhibitory neurons. In somatostatin-expressing inhibitory neurons, one of major subtypes of inhibitory neurons, Reelin-rich protein supplementation induced the phosphorylation of S6. Subsequently, we investigated whether or not Reelin-rich protein supplementation affected dendrite development in cultured inhibitory neurons. Reelin-rich protein supplementation did not change the total length of dendrites in inhibitory neurons in vitro. Finally, we examined the development of inhibitory synapses in primary hippocampal neurons and found that Reelin-rich protein supplementation significantly reduced the density of gephyrin–VGAT-positive clusters in the dendritic regions without changing the expression levels of several inhibitory synapse-related proteins. These findings indicate a new role for Reelin in specific groups of inhibitory neurons and the development of inhibitory synapses, which may contribute to the underlying cellular mechanisms of RELN-associated neurological disorders.
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Bao, Shaowen, Lu Chen, Xiaoxi Qiao y Richard F. Thompson. "Transgenic Brain-Derived Neurotrophic Factor Modulates a Developing Cerebellar Inhibitory Synapse". Learning & Memory 6, n.º 3 (1 de mayo de 1999): 276–83. http://dx.doi.org/10.1101/lm.6.3.276.
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Brain-derived neurotrophic factor (BDNF) has been shown to promote synapse formation and maturation in neurons of many brain regions, including inhibitory synapses. In the cerebellum, the Golgi cell-granule cell GABAergic synaptic responses undergo developmental transition from slow-decaying to fast-decaying kinetics, which parallels a developmental increase of GABAAreceptor α6 subunit expression in the cerebellar granule cells. In culture, BDNF accelerates the expression of GABAA receptor α6 subunit expression in granule cells. Here we examined synaptic GABAA response kinetics in BDNF transgenic mice. The mutant mouse, which carries a BDNF transgene driven by a β-actin promoter, overexpresses BDNF (two- to fivefold increase compared with wild types) in all brain regions. Recordings of the spontaneous GABAA responses indicate that the decay time constant of the GABAergic responses decreases during early postnatal development; this transition is accelerated in the BDNF transgenic mouse. The amplitude of the spontaneous GABAA responses was also larger in the transgenic mouse than in the wild-type mouse. However, the frequency of the spontaneous GABAA responses were not different between the two groups. Our results suggest that BDNF may modulate GABAergic synapse maturation in the cerebellum.
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Gardner, D. "Sets of synaptic currents paired by common presynaptic or postsynaptic neurons". Journal of Neurophysiology 61, n.º 4 (1 de abril de 1989): 845–53. http://dx.doi.org/10.1152/jn.1989.61.4.845.
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1. In the buccal ganglia of Aplysia, presynaptic neurons B4 and B5 produce similar inhibitory postsynaptic currents (PSCs) in several postsynaptic follower cells. Previous work has shown that both duration and amplitude of these PSCs vary, that each parameter may be altered transiently by manipulating presynaptic activity, and that these variations affect synaptic efficacy. 2. To permit synapse-to-synapse comparisons, the mean and coefficient of variation (CV) of both peak conductance (gpeak) and time constant of decay (tau) were determined for sets of synaptic currents evoked by direct intracellular stimulation of presynaptic neurons. For 56 synapses, gpeak = 0.40 +/- 0.33 (SD) microS for a CV of 0.83, and tau = 19.7 +/- 4.0 ms for a CV of 0.20. The synapse-to-synapse variability was within 5% of values obtained from a previous population. 3. The relative contributions of presynaptic and postsynaptic factors to efficacy and variability of PSCs were examined by recordings from two classes of three-cell networks and by comparing values of gpeak and tau at synapses sharing a common presynaptic or postsynaptic neuron. 4. In the first case, paired presynaptic inputs from B4 and B5 converged on a common postsynaptic cell. For 16 examples of this case, mean values of both gpeak and tau recorded in a single follower cell, but produced by different presynaptic neurons, were significantly closer than those recorded in different followers (P less than 0.001). The common postsynaptic cell did not constrain variability of these parameters; CVs for paired synapses were not significantly different from the population (P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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Ali, Heba, Lena Marth y Dilja Krueger-Burg. "Neuroligin-2 as a central organizer of inhibitory synapses in health and disease". Science Signaling 13, n.º 663 (22 de diciembre de 2020): eabd8379. http://dx.doi.org/10.1126/scisignal.abd8379.
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Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.
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Unda, Brianna K., Vickie Kwan y Karun K. Singh. "Neuregulin-1 Regulates Cortical Inhibitory Neuron Dendrite and Synapse Growth through DISC1". Neural Plasticity 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/7694385.
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Cortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth. We found that NRG1 increases inhibitory neuron dendrite complexity and glutamatergic synapse formation onto inhibitory neurons and that this effect is blocked by expression of a dominant negative DISC1 mutant, or DISC1 knockdown. We also discovered that NRG1 treatment increases DISC1 expression and its localization to glutamatergic synapses being made onto cortical inhibitory neurons. Mechanistically, we determined that DISC1 binds ErbB4 within cortical inhibitory neurons. Collectively, these data suggest that a NRG1-ErbB4-DISC1 signalling pathway regulates the development of cortical inhibitory neuron dendrite and synaptic growth. Given that NRG1, ErbB4, and DISC1 are schizophrenia-linked genes, these findings shed light on how independent risk factors may signal in a common developmental pathway that contributes to neural connectivity defects and disease pathogenesis.
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Tate, Kinsley, Brenna Kirk, Alisia Tseng, Abigail Ulffers y Karen Litwa. "Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Developing Neural Circuits in a Model of the Human Fetal Cortex". International Journal of Molecular Sciences 22, n.º 19 (28 de septiembre de 2021): 10457. http://dx.doi.org/10.3390/ijms221910457.
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The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation increases the risk of neurodevelopmental abnormalities. However, there is a lack of research into how specific environmental factors directly impact the developing neural circuitry of the human brain. For example, selective serotonin reuptake inhibitors are commonly used throughout pregnancy to treat depression, yet their impact on the developing fetal brain remains unclear. Recently, human brain models have provided unprecedented access to the critical window of prenatal brain development. In the present study, we used human neurons and cortical spheroids to determine whether the selective serotonin reuptake inhibitor fluoxetine alters neurite and synapse formation and the development of spontaneous activity within neural circuits. We demonstrate that cortical spheroids express serotonin transporter, thus recapitulating the early developmental expression of serotonin transporter associated with cortical pyramidal neurons. Cortical spheroids also appropriately express serotonin receptors, such as synaptic 5-HT2A and glial 5-HT5A. To determine whether fluoxetine can affect developing neural circuits independent of serotonergic innervation from the dorsal and medial raphe nuclei, we treated cortical neurons and spheroids with fluoxetine. Fluoxetine alters neurite formation in a dose-dependent fashion. Intriguingly, in cortical spheroids, neither acute nor chronic fluoxetine significantly altered excitatory synapse formation. However, only acute, but not chronic fluoxetine exposure altered inhibitory synaptogenesis. Finally, fluoxetine reversibly suppresses neuronal activity in a dose-dependent manner. These results demonstrate that fluoxetine can acutely alter synaptic function in developing neural circuits, but the effects were not long-lasting. This work provides a foundation for future studies to combine serotonergic innervation with cortical spheroids and assess the contributions of fluoxetine-induced alterations in serotonin levels to brain development.
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RYBICKA, KRYSTYNA KIELAN y SUSAN B. UDIN. "Connections of contralaterally projecting isthmotectal axons and GABA-immunoreactive neurons in Xenopus tectum: An ultrastructural study". Visual Neuroscience 22, n.º 3 (mayo de 2005): 305–15. http://dx.doi.org/10.1017/s0952523805223064.
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To investigate the circuitry that mediates binocular interactions in the tectum of Xenopus frogs, we have begun to identify the tectal cells that receive ipsilateral eye input relayed via the nucleus isthmi. Isthmotectal axons were labeled with horseradish peroxidase, and thin sections were labeled by postembedding immunogold reaction with antibodies to γ-aminobutyric acid (GABA). Ultrastructural examination reveals that many isthmotectal axons terminate on GABA-immunoreactive dendrites. Other isthmotectal axons contact postsynaptic structures that are unlabeled but have an appearance consistent with previously described GABA-poor zones of GABA-immunoreactive dendrites. We also examined the unlabeled inputs to the dendrites that were postsynaptic to filled isthmotectal axons. The most common nonisthmic inputs to those dendrites were GABA-immunoreactive processes with symmetric morphology. Surprisingly, we found only one input with the retinotectal characteristics of densely packed round, clear vesicles and minimal GABA immunoreactivity. These results indicate that isthmotectal axons synapse onto inhibitory interneurons, that retinotectal and isthmotectal axons do not synapse close to each other on the same dendrites, and that inhibitory connections are the closest neighbors to isthmotectal synapses.
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Levinson, Joshua N., Nadège Chéry, Kun Huang, Tak Pan Wong, Kimberly Gerrow, Rujun Kang, Oliver Prange, Yu Tian Wang y Alaa El-Husseini. "Neuroligins Mediate Excitatory and Inhibitory Synapse Formation". Journal of Biological Chemistry 280, n.º 17 (21 de febrero de 2005): 17312–19. http://dx.doi.org/10.1074/jbc.m413812200.
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Sakimoto, Yuya, Paw Min-Thein Oo, Makoto Goshima, Itsuki Kanehisa, Yutaro Tsukada y Dai Mitsushima. "Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology". International Journal of Molecular Sciences 22, n.º 22 (18 de noviembre de 2021): 12456. http://dx.doi.org/10.3390/ijms222212456.
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The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABAA receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.
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Niraula, Suraj, Shirley ShiDu Yan y Jaichandar Subramanian. "Amyloid pathology impairs experience-dependent inhibitory synaptic plasticity". Journal of Neuroscience, 27 de noviembre de 2023, JN—RM—0702–23. http://dx.doi.org/10.1523/jneurosci.0702-23.2023.
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Alzheimer's disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experiencein vivoin the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by subtle broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.Significance statementUsing multicolorin vivotwo-photon microscopy to capture high-resolution images of excitatory and inhibitory synapses from the same neurons over time, we show that amyloid pathology selectively disrupts experience-dependent adaptation of inhibitory synapses. Furthermore, our findings reveal that local clustering of excitatory and inhibitory synapse loss is disrupted, a deficit that could underlie impaired neuronal activity homeostasis, and plasticity in AD.
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Boxer, Emma E. y Jason Aoto. "Neurexins and their ligands at inhibitory synapses". Frontiers in Synaptic Neuroscience 14 (21 de diciembre de 2022). http://dx.doi.org/10.3389/fnsyn.2022.1087238.
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Since the discovery of neurexins (Nrxns) as essential and evolutionarily conserved synaptic adhesion molecules, focus has largely centered on their functional contributions to glutamatergic synapses. Recently, significant advances to our understanding of neurexin function at GABAergic synapses have revealed that neurexins can play pleiotropic roles in regulating inhibitory synapse maintenance and function in a brain-region and synapse-specific manner. GABAergic neurons are incredibly diverse, exhibiting distinct synaptic properties, sites of innervation, neuromodulation, and plasticity. Different classes of GABAergic neurons often express distinct repertoires of Nrxn isoforms that exhibit differential alternative exon usage. Further, Nrxn ligands can be differentially expressed and can display synapse-specific localization patterns, which may contribute to the formation of a complex trans-synaptic molecular code that establishes the properties of inhibitory synapse function and properties of local circuitry. In this review, we will discuss how Nrxns and their ligands sculpt synaptic inhibition in a brain-region, cell-type and synapse-specific manner.