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1
DAVIS, R. E. "Neurophysiology of glutamatergic signalling and anthelmintic action in Ascaris suum: pharmacological evidence for a kainate receptor." Parasitology 116, no. 5 (May 1998): 471–86. http://dx.doi.org/10.1017/s0031182098002467.
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Electrophysiological and pharmacological techniques were used to study glutamatergic signalling in the parasitic nematode, Ascaris suum. Glutamate or kainate injections into whole worms produced a paralysed quasi-static posture similar to the waveform in behaving worms. The DE2 motorneuron class is a primary target. Several glutamatergic substances produced pronounced conductance increases and depolarization in DE2; domoate and kainate were the most potent agonists tested. Glutamate responses and spontaneous excitatory post-synaptic potentials in DE2 were reversibly blocked in sodium-free saline. DE2 sensitivity to exogenous glutamate was sustained during block of synaptic transmission suggesting that glutamatergic receptors are located on DE2 neurons. The glutamate-induced response was localized to the DE2 dendrite, coincident with the synapses responsible for spontaneous potentials in DE2. Steady-state potentials reached during glutamate superfusion were similar to the reversal potentials for both the spontaneous post-synaptic potentials and glutamate, also suggesting that these potentials may be glutamatergic. Non-N-methyl-D-aspartate receptor antagonists partially blocked spontaneous DE2 excitatory potentials and responses elicited by exogenous glutamate and kainate. This glutamatergic pathway may play a role in nematode locomotory behaviour and account for the paralysing anthelmintic action of excitatory amino acid analogues like kainate and domoate.
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Duric, Vanja, Mounira Banasr, Craig A. Stockmeier, Arthur A. Simen, Samuel S. Newton, James C. Overholser, George J. Jurjus, Lesa Dieter, and Ronald S. Duman. "Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects." International Journal of Neuropsychopharmacology 16, no. 1 (February 1, 2013): 69–82. http://dx.doi.org/10.1017/s1461145712000016.
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Abstract Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.
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Choi, In-Ae, Ji Hee Yun, Ji-Hye Kim, Hahn Young Kim, Dong-Hee Choi, and Jongmin Lee. "Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke." International Journal of Molecular Sciences 20, no. 24 (December 16, 2019): 6349. http://dx.doi.org/10.3390/ijms20246349.
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To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology analyses, followed by string analysis of the protein–protein interactions (PPI) of the products of these genes. We found 3771, 536, and 533 DEGs at 1, 4, and 8 weeks after stroke, respectively. A marked decrease in biological–process categories, such as brain development and memory, and a decrease in neurotransmitter synaptic and signaling pathways were observed 1 week after stroke. The PPI analysis showed the downregulation of Dlg4, Bdnf, Gria1, Rhoa, Mapk8, and glutamatergic receptors. An increase in biological–process categories, including cell population proliferation, cell adhesion, and inflammatory responses, was detected at 4 and 8 weeks post-stroke. The KEGG pathways of complement and coagulation cascades, phagosomes, antigen processing, and antigen presentation were also altered. CD44, C1, Fcgr2b, Spp1, and Cd74 occupied a prominent position in network analyses. These time-dependent changes in gene profiles reveal the unique pathophysiological characteristics of stroke and suggest new therapeutic targets for this disease.
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Kreyden, Victoria A., Elly B. Mawi, Kristen M. Rush, and Jennifer R. Kowalski. "UBC-9 Acts in GABA Neurons to Control Neuromuscular Signaling in C. elegans." Neuroscience Insights 15 (January 2020): 263310552096279. http://dx.doi.org/10.1177/2633105520962792.
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Regulation of excitatory to inhibitory signaling balance is essential to nervous system health and is maintained by numerous enzyme systems that modulate the activity, localization, and abundance of synaptic proteins. SUMOylation is a key post-translational regulator of protein function in diverse cells, including neurons. There, its role in regulating synaptic transmission through pre- and postsynaptic effects has been shown primarily at glutamatergic central nervous system synapses, where the sole SUMO-conjugating enzyme Ubc9 is a critical player. However, whether Ubc9 functions globally at other synapses, including inhibitory synapses, has not been explored. Here, we investigated the role of UBC-9 and the SUMOylation pathway in controlling the balance of excitatory cholinergic and inhibitory GABAergic signaling required for muscle contraction in Caenorhabditis elegans. We found inhibition or overexpression of UBC-9 in neurons modestly increased muscle excitation. Similar and even stronger phenotypes were seen with UBC-9 overexpression specifically in GABAergic neurons, but not in cholinergic neurons. These effects correlated with accumulation of synaptic vesicle-associated proteins at GABAergic presynapses, where UBC-9 and the C. elegans SUMO ortholog SMO-1 localized, and with defects in GABA-dependent behaviors. Experiments involving expression of catalytically inactive UBC-9 [UBC-9(C93S)], as well as co-expression of UBC-9 and SMO-1, suggested wild type UBC-9 overexpressed alone may act via substrate sequestration in the absence of sufficient free SUMO, underscoring the importance of tightly regulated SUMO enzyme function. Similar effects on muscle excitation, GABAergic signaling, and synaptic vesicle localization occurred with overexpression of the SUMO activating enzyme subunit AOS-1. Together, these data support a model in which UBC-9 and the SUMOylation system act at presynaptic sites in inhibitory motor neurons to control synaptic signaling balance in C. elegans. Future studies will be important to define UBC-9 targets at this synapse, as well as mechanisms by which UBC-9 and the SUMO pathway are regulated.
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Leahy, Shannon N., Chunzhu Song, Dominic J. Vita, and Kendal Broadie. "FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission." PLOS Biology 21, no. 1 (January 26, 2023): e3001969. http://dx.doi.org/10.1371/journal.pbio.3001969.
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Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength.
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Vanover, Kimberly, Steven Glass, Susan Kozauer, Jelena Saillard, Juan Sanchez, Michal Weingart, Sharon Mates, Andrew Satlin, and Robert Davis. "30 Lumateperone (ITI-007) for the Treatment of Schizophrenia: Overview of Placebo-Controlled Clinical Trials and an Open-label Safety Switching Study." CNS Spectrums 24, no. 1 (February 2019): 190–91. http://dx.doi.org/10.1017/s1092852919000245.
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AbstractBackgroundLumateperone is a first-in-class agent in development for schizophrenia that acts synergistically through serotonergic, dopaminergic and glutamatergic systems. Lumateperone is a potent 5-HT2A antagonist, a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonist and post-synaptic antagonist activity at D2, a glutamate GluN2B receptor phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway and an inhibitor of serotonin reuptake.MethodsLumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. The primary endpoint was change from baseline on the PANSS total score compared to placebo. In Study ‘005, 335 patients were randomized to receive ITI-007 60mg or 120mg , risperidone 4mg (active control) or placebo QAM for 4weeks. In Study ‘301, 450 patients were randomized to receive ITI-007 60mg or 40mg , or placebo QAM for 4weeks. In Study ‘302, 696 patients were randomized to receive ITI-007 60mg or 20mg , risperidone 4mg (active control) or placebo QAM for 6weeks. Also, an open-label safety switching study was conducted in which 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6weeks with lumateperone QPM and then switched back to SOC.ResultsIn Studies ‘005 and ‘301, lumateperone (60mg ITI-007) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28. In Study ‘302, neither dose of lumateperone separated from placebo on the primary endpoint; a high placebo response was observed in this study. Across all 3 efficacy trials, lumateperone improved symptoms of schizophrenia with the same trajectory and same magnitude of improvement from baseline to endpoint on the PANSS total score.Lumateperone was well-tolerated with a favorable safety profile in all studies. In the two studies with risperidone included as an active control, lumateperone was statistically significantly better than risperidone on key safety and tolerability measures. In the open-label safety switching study statistically significant improvements from SOC were observed in body weight, cardiometabolic and endocrine parameters worsened again when switched back to SOC medication. In this study, symptoms of schizophrenia generally remained stable or improved. Greater improvements were observed in subgroups of patients with elevated symptomatology (comorbid symptoms of depression and those with prominent negative symptoms).DiscussionLumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of cardiometabolic and motor safety issues presents a safety profile differentiated from standard-of-care antipsychotic therapy.Funding Acknowledgements: Intra-Cellular Therapies, Inc.
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Rosenbrock, Holger, Katja Kroker, Birgit Stierstorfer, Scott Hobson, Roberto Arban, and Cornelia Dorner-Ciossek. "S31. ENHANCEMENT OF SYNAPTIC PLASTICITY BY COMBINATION OF PDE2 AND PDE9 INHIBITION PRESUMABLY VIA PRE- AND POST-SYNAPTIC MECHANISMS." Schizophrenia Bulletin 46, Supplement_1 (April 2020): S43. http://dx.doi.org/10.1093/schbul/sbaa031.097.
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Abstract Background Evidence from clinical and preclinical studies has led to the hypothesis that impaired glutamatergic transmission and NMDA receptor hypofunction play an important role in cognitive impairment associated with schizophrenia (CIAS). Second messenger pathways depending on cAMP and/or cGMP are key regulators of glutamatergic transmission and NMDA receptor related pathways. Therefore, the specific cyclic nucleotide phosphodiesterases (PDEs) PDE2 and PDE9, expressed in cognition relevant brain regions such as cortex and hippocampus, are putative targets for cognition enhancement in neuropsychiatric disorders (Dorner-Ciossek et al., 2017; Zhang et al., 2017). In fact, it has previously been shown that either PDE2 or PDE9 inhibition increases synaptic plasticity, as determined by hippocampal long-term potentiation (LTP), and improves memory performance in animal cognition tasks. However, the exact sub-cellular localization of PDE2 and PDE9 enzymes in neurons is not fully established. Thus, in the present study, co-localization studies of PDE2 and PDE9 with pre- and post-synaptic markers were performed by double immunofluorescence staining. Moreover, the PDE2 inhibitor PF-05180999 (Helal et al., 2018) was characterized regarding enhancement of hippocampal LTP and further investigated in combination with the PDE9 inhibitor Bay 73–6691 (Wunder et al., 2005) for potential synergistic effects on LTP. Methods Brains of adult rats were fixed with formalin and sliced for double immunofluorescence staining of PDE2 or PDE9 enzymes with pre-/post-synaptic markers. Analysis of staining was performed by confocal microscopy. Effects of the PDE2 inhibitor PF-05180999 alone and in combination with the PDE9 inhibitor Bay 73–6691 on synaptic plasticity were evaluated in rat hippocampal slices by using a protein-synthesis independent early LTP paradigm. Results Double immunofluorescence analysis revealed co-localization of PDE2 predominantly with pre-synaptic, but not post-synaptic, markers and mainly in glutamatergic neurons. In contrast, PDE9 showed co-localization with post-synaptic markers. Inhibition of PDE2 by PF-05180999 led to a concentration-dependent enhancement of early LTP. Combination of PF-05180999 with a subthreshold concentration of the PDE9 inhibitor Bay 73–6691 caused a transformation from early LTP into protein-synthesis dependent late LTP. Discussion Immunofluorescence staining suggests that PDE2 is localized pre-synaptically in glutamatergic neurons. This might indicate an involvement of PDE2 in neurotransmitter release via regulating cGMP/cAMP levels at pre-synaptic terminals, whereas PDE9 is located post-synaptically presumably involved in the NMDA receptor signaling cascade via regulation of cGMP. Corroborating previous findings, PDE2 inhibition improves synaptic plasticity as shown by enhanced LTP. Moreover, for the first time, we could show that the combination of a PDE2 with a PDE9 inhibitor acts synergistically on improvement of synaptic plasticity as demonstrated by the shift from early into late LTP, which is considered to be a crucial mechanism for memory formation. References
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Colombo and Francolini. "Glutamate at the Vertebrate Neuromuscular Junction: From Modulation to Neurotransmission." Cells 8, no. 9 (August 28, 2019): 996. http://dx.doi.org/10.3390/cells8090996.
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Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in modulating cholinergic transmission and plastic changes in the last. Presynaptic terminals of neuromuscular junctions contain and release glutamate that contribute to the regulation of synaptic neurotransmission through its interaction with pre- and post-synaptic receptors activating downstream signaling pathways that tune synaptic efficacy and plasticity. During vertebrate development, the chemical nature of the neurotransmitter at the vertebrate neuromuscular junction can be experimentally shifted from acetylcholine to other mediators (including glutamate) through the modulation of calcium dynamics in motoneurons and, when the neurotransmitter changes, the muscle fiber expresses and assembles new receptors to match the nature of the new mediator. Finally, in adult rodents, by diverting descending spinal glutamatergic axons to a denervated muscle, a functional reinnervation can be achieved with the formation of new neuromuscular junctions that use glutamate as neurotransmitter and express ionotropic glutamate receptors and other markers of central glutamatergic synapses. Here, we summarize the past and recent experimental evidences in support of a role of glutamate as a mediator at the synapse between the motor nerve ending and the skeletal muscle fiber, focusing on the molecules and signaling pathways that are present and activated by glutamate at the vertebrate neuromuscular junction.
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Losada-Pérez, María, Mamen Hernández García-Moreno, Irene García-Ricote, and Sergio Casas-Tintó. "Synaptic components are required for glioblastoma progression in Drosophila." PLOS Genetics 18, no. 7 (July 25, 2022): e1010329. http://dx.doi.org/10.1371/journal.pgen.1010329.
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Glioblastoma (GB) is the most aggressive, lethal and frequent primary brain tumor. It originates from glial cells and is characterized by rapid expansion through infiltration. GB cells interact with the microenvironment and healthy surrounding tissues, mostly neurons and vessels. GB cells project tumor microtubes (TMs) contact with neurons, and exchange signaling molecules related to Wingless/WNT, JNK, Insulin or Neuroligin-3 pathways. This cell to cell communication promotes GB expansion and neurodegeneration. Moreover, healthy neurons form glutamatergic functional synapses with GB cells which facilitate GB expansion and premature death in mouse GB xerograph models. Targeting signaling and synaptic components of GB progression may become a suitable strategy against glioblastoma. In a Drosophila GB model, we have determined the post-synaptic nature of GB cells with respect to neurons, and the contribution of post-synaptic genes expressed in GB cells to tumor progression. In addition, we document the presence of intratumoral synapses between GB cells, and the functional contribution of pre-synaptic genes to GB calcium dependent activity and expansion. Finally, we explore the relevance of synaptic genes in GB cells to the lifespan reduction caused by GB advance. Our results indicate that both presynaptic and postsynaptic proteins play a role in GB progression and lethality.
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Mawey, Feytie Magda, Azimatul Karimah, Erlyn Limoa, and Muhammad Nazmuddin. "Neuroinflammation in Schizophrenia." Jurnal Psikiatri Surabaya 10, no. 1 (May 31, 2021): 1. http://dx.doi.org/10.20473/jps.v10i1.20871.
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Schizophrenia is a chronic debilitating mental illness. In many aspects, the neuropathology of schizophrenia is closely associated with neuroinflammation, especially microglial activation. Microglial hyperactivity, which is characterized by the predominant release of proinflammatory cytokines serves as the basis of the neuroinflammation hypothesis in schizophrenia. The enhanced inflammatory induce neuronal susceptibility to oxidative stress and trigger, glutamatergic synaptic dysregulation, especially in the mesolimbic and mesocortical pathways. Many in vitro studies, in vivo animal evidence, post-mortem examinations, neuroimaging evaluations with Positron Emission Tomography (PET), anti-inflammatory and antipsychotic use converge upon the central role of microglial activation and proinflammatory cytokines as common of features schizophrenia.
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Martinez De La Cruz, Braulio, Robert Markus, Sunir Malla, Maria Isabel Haig, Chris Gell, Fei Sang, Eleanor Bellows, et al. "Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging." Molecular Psychiatry 26, no. 12 (October 19, 2021): 7141–53. http://dx.doi.org/10.1038/s41380-021-01282-z.
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AbstractSynaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.
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Coletto, L. A., F. Ingegnoli, C. Cambria, L. Cantone, O. De Lucia, R. Caporali, V. Bollati, M. Buoli, and F. Antonucci. "POS0430 SYNOVIAL FLUID-DERIVED EXTRACELLULAR VESICLES FROM RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS MODULATE DIFFERENT HIPPOCAMPAL SYNAPTIC ACTIVITIES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 469.2–470. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3188.
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BackgroundAccumulating evidence suggests that poor mental health is one of the most common comorbidities of both rheumatoid arthritis (RA) and osteoarthritis (OA) [1]. Even if underpinning RA and OA are different genetic, structural, mechanical, and immunologic pathways involved in their pathogenesis, poor mental health, and joint involvement are intertwined and negatively affect their mutual course by contributing to global disability. Thus, new insights into mechanisms that link these disorders are needed to identify new actionable biomarkers to drive more personalized therapeutic strategies. Amidst potential mediators, extracellular vesicles (EVs) play a central role in terms of communication between cells, they cross the blood-brain barrier and based on their cargos can affect the recipient cell function [2].ObjectivesTo isolate EVs from synovial fluid (SF) in RA and OA patients and to evaluate if and how these EVs can alter in vitro synaptic transmission of murine hippocampal neurons.MethodsIn this cross-sectional pilot study, consecutive adult RA and primary OA who were referred to the Rheumatology Unit for aspiration of joint effusion were enrolled. Demographic and clinical variables and mental health rating scales were collected. Discarded SF were collected and EVs were isolated and analyzed by Malvern NanoSight NS300 system to obtain information on their number and size. Afterwards, DIV14 cultured wild-type hippocampal neurons were exposed for two hours to OA- and RA-EVs at low and high concentration EVs. Thus, miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs), which reflects glutamatergic and GABA-ergic activity respectively, were examined by exploiting patch-clamp recordings in the whole-cell configuration. Frequency and amplitude were analyzed to evaluate potential changes at the presynaptic or postsynaptic compartment. Mann Whitney test was used to compare two different samples.ResultsEight RA patients (7 female, mean age 57 yrs), and 5 primary OA (4 female, mean age 60 yrs) were recruited for SF aspiration. The mean VAS pain was 7.25 in RA and 6.5 in OA. No statistically significant differences were found between the two groups in mean rating scale scores although patients affected by RA had more severe depressive symptoms (Montgomery Asberg Depression Rating Scale -MADRS- means scores: 16.57) with respect OA group (MADRS mean scores: 10). The Nanoparticle tracking analysis showed that RA-EVs were significantly more in number compared to OA-EVs (Figure 1 A), mimicking more inflammation, while no significant difference in size was observed. Analysis of miniature events revealed the occurrence of two different changes. High concentration of OA-EVs has led to an increased amplitude of excitatory events, meaning an increased susceptibility of neurons to glutamate in the post-synaptic compartment (Figure 1 B). Whereas low concentration of RA-EVs has led to a decreased frequency of inhibitory events, which reflects a reduced function of GABA-ergic synapse in the pre-synaptic compartment (Figure 1 C).Figure 1.ConclusionOur results suggest that SF-derived EVs from OA and RA patients lead to different specific changes of neurotransmission, with different concentration needed to alter neuronal spontaneous activity in post-synaptic and pre-synaptic compartment, respectively. EVs may provide insight into the pathogenesis of joint-brain communication in RA and OA, unraveling specific pathways thus allowing targeted therapies for neuropsychiatric involvement.References[1]Lancet 2017;390(10100): 1211–1259[2]FASEB Bioadv 2021;3(9):665-675Disclosure of InterestsLavinia A. Coletto: None declared, Francesca Ingegnoli: None declared, Clara Cambria: None declared, Laura Cantone: None declared, Orazio De Lucia: None declared, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, Fresenius-Kabi, MSD, UCB, Roche,Janssen, Novartis, Sandoz, Consultant of: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, MSD, UCB, Janssen, Novartis, Sandoz, Valentina Bollati: None declared, Massimiliano Buoli: None declared, Flavia Antonucci: None declared.
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Turitskaya, T. G., S. N. Lukashev, V. P. Lyashenko, and G. G. Sidorenko. "The features of summary background electric activity of the hypothalamus of rats under conditions of chronic caffeine alimentation." Regulatory Mechanisms in Biosystems 9, no. 3 (August 17, 2018): 417–25. http://dx.doi.org/10.15421/021862.
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One of the factors of the environment which essentially shifts homeostasis is diets which contain caffeine. The aim of the study was to find out the basic characteristics of background electrical activity of trophotrophic and ergotrophic zones of the hypothalamus in conditions of chronic caffeine alimentation. Experiments were carried out on non-linear white male rats. The first group consisted of control animals (n = 22). The second group (n = 24) was represented by the animals that were given pure caffeine in an amount of 150 mg/kg/day with their meal. The registration on a electrohypothalamogram was carried out in conditions of acute experiment, every 2 weeks for 12 weeks. The spectral (mkV2) and the normalized power (%) of electrohypothalamogram waves were analyzed within the common frequency band. The analysis of the results allowed us to establish a certain specificity of the reaction of the neuronal system of the trophotropic and ergotropic zones of the rat hypothalamus to the effect of chronic caffeine alimentation. The main difference in the reactive state of electrophysiological indices in the trophotrophic zone of rats is the lack of a typical desynchronization from the 4th to the 8th week of the study and the hypersynchronization after 12 weeks of the experiment. The most probable mechanism that explains the results obtained is the ultra-powerful GABA-ergic modulation of this zone, the main energy-accumulating center. Perhaps, this powerful inhibitory resource in this cerebral locus is the main stress-limiting factor that makes this zone of the central nervous system of rats less sensitive to caffeine exposure. Instead, under the influence of chronic caffeine load in the ergotropic zone of the hypothalamus, after 6 weeks of the experiment desynchronous high-frequency rhythms dominated. During the subsequent time of the experiment, we observed a decrease in both low-frequency and high-frequency components of the electrohypothalamogram of this zone. This gives reason to assume that the key component of the neurophysiological response of the posterior hypothalamus of rats to the caffeine ration is the powerful glutamatergic effects on the pre-synaptic and post-synaptic neurons under conditions of reactive exhaustion of local neurosynthetics. Caffeine depletion of the hypothalamic neurotransmission at the end of the experiment is replaced by an effective adaptive ergotropic restoration of neurosynthetic activity in this locus of the central nervous system of rats. Thus, caffeine has a powerful activating effect on the ergotropic function of the posterior hypothalamus of rats. Such a difference in the chronic effect of caffeine on the trophotropic and ergotropic zone of the rat hypothalamus is primarily due to the different mediator support of these zones underlying their physiological purpose. GABA is the main mediator of the trophotropic zone and the main neurotransmitter of its synchronous activity. At the same time, neurotransmitter support of the ergotropic zone is represented by glutamate, which, along with other agents, implements its desynchronous activity. Since caffeine stimulates excitation, activating the pathways traditionally associated with motivational and motor reactions in the brain, it can be assumed that this explains the fact of a more powerful influence of caffeine precisely on the ergotrophic zone of the hypothalamus.
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Chen, Chuyu, Giulia Soto, Vasin Dumrongprechachan, Nicholas Bannon, Shuo Kang, Yevgenia Kozorovitskiy, and Loukia Parisiadou. "Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations." eLife 9 (October 2, 2020). http://dx.doi.org/10.7554/elife.58997.
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LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose toward disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using two-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset.
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Chen, Li-Jin, Jeng-Rung Chen, and Guo-Fang Tseng. "Modulation of striatal glutamatergic, dopaminergic and cholinergic neurotransmission pathways concomitant with motor disturbance in rats with kaolin-induced hydrocephalus." Fluids and Barriers of the CNS 19, no. 1 (November 27, 2022). http://dx.doi.org/10.1186/s12987-022-00393-1.
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Abstract Background Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid in the cerebral ventricles and causes motor impairments. The mechanisms underlying the motor changes remain elusive. Enlargement of ventricles compresses the striatum of the basal ganglia, a group of nuclei involved in the subcortical motor circuit. Here, we used a kaolin-injection juvenile rat model to explore the effects of acute and chronic hydrocephalus, 1 and 5 weeks post-treatment, respectively on the three major neurotransmission pathways (glutamatergic, dopaminergic and cholinergic) in the striatum. Methods Rats were evaluated for motor impairments. Expressions of presynaptic and postsynaptic protein markers related to the glutamatergic, dopaminergic, and cholinergic connections in the striatum were evaluated. Combined intracellular dye injection and substance P immunohistochemistry were used to distinguish between direct and indirect pathway striatal medium spiny neurons (d and i-MSNs) for the analysis of their dendritic spine density changes. Results Hydrocephalic rats showed compromised open-field gait behavior. However, male but not female rats displayed stereotypic movements and compromised rotarod performance. Morphologically, the increase in lateral ventricle sizes was greater in the chronic than acute hydrocephalus conditions. Biochemically, hydrocephalic rats had significantly decreased striatal levels of synaptophysin, vesicular glutamate transporter 1, and glutamatergic postsynaptic density protein 95, suggesting a reduction of corticostriatal excitation. The expression of GluR2/3 was also reduced suggesting glutamate receptor compositional changes. The densities of dendritic spines, morphological correlates of excitatory synaptic foci, on both d and i-MSNs were also reduced. Hydrocephalus altered type 1 (DR1) and 2 (DR2) dopamine receptor expressions without affecting tyrosine hydroxylase level. DR1 was decreased in acute and chronic hydrocephalus, while DR2 only started to decrease later during chronic hydrocephalus. Since dopamine excites d-MSNs through DR1 and inhibits i-MSNs via DR2, our findings suggest that hydrocephalus downregulated the direct basal ganglia neural pathway persistently and disinhibited the indirect pathway late during chronic hydrocephalus. Hydrocephalus also persistently reduced the striatal choline acetyltransferase level, suggesting a reduction of cholinergic modulation. Conclusions Hydrocephalus altered striatal glutamatergic, dopaminergic, and cholinergic neurotransmission pathways and tipped the balance between the direct and indirect basal ganglia circuits, which could have contributed to the motor impairments in hydrocephalus.
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Narita, Minoru, Keisuke Hashimoto, Taku Amano, Michiko Narita, Keiichi Niikura, Atsushi Nakamura, and Tsutomu Suzuki. "Post-synaptic action of morphine on glutamatergic neuronal transmission related to the descending antinociceptive pathway in the rat thalamus." Journal of Neurochemistry, November 12, 2007, 071115085713011—??? http://dx.doi.org/10.1111/j.1471-4159.2007.05059.x.
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Laszlo, Zsofia I., Nicole Hindley, Anna Sanchez Avila, Rachel A. Kline, Samantha L. Eaton, Douglas J. Lamont, Colin Smith, Tara L. Spires-Jones, Thomas M. Wishart, and Christopher M. Henstridge. "Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex." Acta Neuropathologica Communications 10, no. 1 (October 29, 2022). http://dx.doi.org/10.1186/s40478-022-01455-z.
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AbstractIncreasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.
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Chatterjee, Rounak, Janet L. Paluh, Souradeep Chowdhury, Soham Mondal, Arnab Raha, and Amitava Mukherjee. "SyNC, a Computationally Extensive and Realistic Neural Net to Identify Relative Impacts of Synaptopathy Mechanisms on Glutamatergic Neurons and Their Networks in Autism and Complex Neurological Disorders." Frontiers in Cellular Neuroscience 15 (July 20, 2021). http://dx.doi.org/10.3389/fncel.2021.674030.
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Synaptic function and experience-dependent plasticity across multiple synapses are dependent on the types of neurons interacting as well as the intricate mechanisms that operate at the molecular level of the synapse. To understand the complexity of information processing at synaptic networks will rely in part on effective computational models. Such models should also evaluate disruptions to synaptic function by multiple mechanisms. By co-development of algorithms alongside hardware, real time analysis metrics can be co-prioritized along with biological complexity. The hippocampus is implicated in autism spectrum disorders (ASD) and within this region glutamatergic neurons constitute 90% of the neurons integral to the functioning of neuronal networks. Here we generate a computational model referred to as ASD interrogator (ASDint) and corresponding hardware to enable in silicon analysis of multiple ASD mechanisms affecting glutamatergic neuron synapses. The hardware architecture Synaptic Neuronal Circuit, SyNC, is a novel GPU accelerator or neural net, that extends discovery by acting as a biologically relevant realistic neuron synapse in real time. Co-developed ASDint and SyNC expand spiking neural network models of plasticity to comparative analysis of retrograde messengers. The SyNC model is realized in an ASIC architecture, which enables the ability to compute increasingly complex scenarios without sacrificing area efficiency of the model. Here we apply the ASDint model to analyse neuronal circuitry dysfunctions associated with autism spectral disorder (ASD) synaptopathies and their effects on the synaptic learning parameter and demonstrate SyNC on an ideal ASDint scenario. Our work highlights the value of secondary pathways in regard to evaluating complex ASD synaptopathy mechanisms. By comparing the degree of variation in the synaptic learning parameter to the response obtained from simulations of the ideal scenario we determine the potency and time of the effect of a particular evaluated mechanism. Hence simulations of such scenarios in even a small neuronal network now allows us to identify relative impacts of changed parameters and their effect on synaptic function. Based on this, we can estimate the minimum fraction of a neuron exhibiting a particular dysfunction scenario required to lead to complete failure of a neural network to coordinate pre-synaptic and post-synaptic outputs.
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Pascual Cuadrado, Diego, Anna Wierczeiko, Charlotte Hewel, Susanne Gerber, and Beat Lutz. "Dichotomic Hippocampal Transcriptome After Glutamatergic vs. GABAergic Deletion of the Cannabinoid CB1 Receptor." Frontiers in Synaptic Neuroscience 13 (April 8, 2021). http://dx.doi.org/10.3389/fnsyn.2021.660718.
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Brain homeostasis is the dynamic equilibrium whereby physiological parameters are kept actively within a specific range. The homeostatic range is not fixed and may change throughout the individual's lifespan, or may be transiently modified in the presence of severe perturbations. The endocannabinoid system has emerged as a safeguard of homeostasis, e.g., it modulates neurotransmission and protects neurons from prolonged or excessively strong activation. We used genetically engineered mouse lines that lack the cannabinoid type-1 receptor (CB1) either in dorsal telencephalic glutamatergic or in forebrain GABAergic neurons to create new allostatic states, resulting from alterations in the excitatory/inhibitory (E/I) balance. Previous studies with these two mouse lines have shown dichotomic results in the context of behavior, neuronal morphology, and electrophysiology. Thus, we aimed at analyzing the transcriptomic profile of the hippocampal CA region from these mice in the basal condition and after a mild behavioral stimulation (open field). Our results provide insights into the gene networks that compensate chronic E/I imbalances. Among these, there are differentially expressed genes involved in neuronal and synaptic functions, synaptic plasticity, and the regulation of behavior. Interestingly, some of these genes, e.g., Rab3b, Crhbp, and Kcnn2, and related pathways showed a dichotomic expression, i.e., they are up-regulated in one mutant line and down-regulated in the other one. Subsequent interrogation on the source of the alterations at transcript level were applied using exon-intron split analysis. However, no strong directions toward transcriptional or post-transcriptional regulation comparing both mouse lines were observed. Altogether, the dichotomic gene expression observed and their involved signaling pathways are of interest because they may act as “switches” to modulate the directionality of neural homeostasis, which then is relevant for pathologies, such as stress-related disorders and epilepsy.
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Aponte-Santiago, Nicole A., and J. Troy Littleton. "Synaptic Properties and Plasticity Mechanisms of Invertebrate Tonic and Phasic Neurons." Frontiers in Physiology 11 (December 16, 2020). http://dx.doi.org/10.3389/fphys.2020.611982.
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Defining neuronal cell types and their associated biophysical and synaptic diversity has become an important goal in neuroscience as a mechanism to create comprehensive brain cell atlases in the post-genomic age. Beyond broad classification such as neurotransmitter expression, interneuron vs. pyramidal, sensory or motor, the field is still in the early stages of understanding closely related cell types. In both vertebrate and invertebrate nervous systems, one well-described distinction related to firing characteristics and synaptic release properties are tonic and phasic neuronal subtypes. In vertebrates, these classes were defined based on sustained firing responses during stimulation (tonic) vs. transient responses that rapidly adapt (phasic). In crustaceans, the distinction expanded to include synaptic release properties, with tonic motoneurons displaying sustained firing and weaker synapses that undergo short-term facilitation to maintain muscle contraction and posture. In contrast, phasic motoneurons with stronger synapses showed rapid depression and were recruited for short bursts during fast locomotion. Tonic and phasic motoneurons with similarities to those in crustaceans have been characterized in Drosophila, allowing the genetic toolkit associated with this model to be used for dissecting the unique properties and plasticity mechanisms for these neuronal subtypes. This review outlines general properties of invertebrate tonic and phasic motoneurons and highlights recent advances that characterize distinct synaptic and plasticity pathways associated with two closely related glutamatergic neuronal cell types that drive invertebrate locomotion.
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Aponte-Santiago, Nicole A., and J. Troy Littleton. "Synaptic Properties and Plasticity Mechanisms of Invertebrate Tonic and Phasic Neurons." Frontiers in Physiology 11 (December 16, 2020). http://dx.doi.org/10.3389/fphys.2020.611982.
Full textAbstract:
Defining neuronal cell types and their associated biophysical and synaptic diversity has become an important goal in neuroscience as a mechanism to create comprehensive brain cell atlases in the post-genomic age. Beyond broad classification such as neurotransmitter expression, interneuron vs. pyramidal, sensory or motor, the field is still in the early stages of understanding closely related cell types. In both vertebrate and invertebrate nervous systems, one well-described distinction related to firing characteristics and synaptic release properties are tonic and phasic neuronal subtypes. In vertebrates, these classes were defined based on sustained firing responses during stimulation (tonic) vs. transient responses that rapidly adapt (phasic). In crustaceans, the distinction expanded to include synaptic release properties, with tonic motoneurons displaying sustained firing and weaker synapses that undergo short-term facilitation to maintain muscle contraction and posture. In contrast, phasic motoneurons with stronger synapses showed rapid depression and were recruited for short bursts during fast locomotion. Tonic and phasic motoneurons with similarities to those in crustaceans have been characterized in Drosophila, allowing the genetic toolkit associated with this model to be used for dissecting the unique properties and plasticity mechanisms for these neuronal subtypes. This review outlines general properties of invertebrate tonic and phasic motoneurons and highlights recent advances that characterize distinct synaptic and plasticity pathways associated with two closely related glutamatergic neuronal cell types that drive invertebrate locomotion.
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Burlando, Bruno, Viviana Mucci, Cherylea J. Browne, Serena Losacco, Iole Indovina, Lucio Marinelli, Franco Blanchini, and Giulia Giordano. "Mal de Debarquement Syndrome explained by a vestibulo–cerebellar oscillator." Mathematical Medicine and Biology: A Journal of the IMA, December 5, 2022. http://dx.doi.org/10.1093/imammb/dqac016.
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Abstract Mal de Debarquement Syndrome (MdDS) is a puzzling central vestibular disorder characterized by a long-lasting perception of oscillatory postural instability that may occur after sea travels or flights. We have postulated that MdDS originates from the post-disembarking persistence of an adaptive internal oscillator consisting of a loop system, involving the right and left vestibular nuclei, and the Purkinje cells of the right and left flocculonodular cerebellar cortex, connected by GABAergic and glutamatergic fibers. We have formulated here a mathematical model of the vestibulo–cerebellar loop system and carried out a computational analysis based on a set of differential equations describing the interactions among the loop elements and containing Hill functions that model input–output firing rates relationships among neurons. The analysis indicates that the system acquires a spontaneous and permanent oscillatory behavior for a decrease of threshold and an increase of sensitivity in neuronal input–output responses. These results suggest a role for synaptic plasticity in MdDS pathophysiology, thus reinforcing our previous hypothesis that MdDS may be the result of excessive synaptic plasticity acting on the vestibulo–cerebellar network during its entraining to an oscillatory environment. Hence, our study points to neuroendocrine pathways that lead to increased synaptic response as possible new therapeutic targets for the clinical treatment of the disorder.
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Abraham, Joseph R., Nicholas Szoko, John Barnard, Robert A. Rubin, Daniela Schlatzer, Kathleen Lundberg, Xiaolin Li, and Marvin R. Natowicz. "Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes." Scientific Reports 9, no. 1 (September 11, 2019). http://dx.doi.org/10.1038/s41598-019-49533-y.
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Abstract Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.