A Specific Neuroligin3-αNeurexin1Signaling Regulates GABAergic Synaptic Function in Mouse Hippocampus
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ABSTRACT:
PROVIDER: PRJNA634328 | ENA |
REPOSITORIES: ENA
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Project description:Synapses are fundamental organizers of precise signal propagation between neurons. Maintaining synapse assemblies require interactions between pre- and post- synaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the function of Neuroligins (Nlgn1 - 4), postsynaptic CAMs, relies on the formation of trans-synaptic complexes with Neurexins (Nrxs), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated through Nrx interaction is mostly unknown. Here, we find for the first time that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3 (VGT3)-expressing inhibitory terminals. Overexpression and knockdown approaches indicate that Nlgn3 regulates VGT3-positive inhibitory interneuron-mediated synaptic transmission. Fluorescent in situ hybridization and single-cell RNA sequencing studies revealed that αNrxn1 and βNrxn3 are VGT3 interneuron-specific Nrxn isoforms and the expression levels of Nrxn splice isoforms are highly diverse in VGT3 interneurons, respectively. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrx1+AS4 expressed in VGT3-positive interneurons to regulate inhibitory synaptic transmission. Our results strongly suggest that specific Nlgn-Nrx interaction generate distinct functional properties at synapses.
2021-01-04 | GSE150989 | GEO
Project description:Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the ?Nrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic ?Nrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.
| S-EPMC7758064 | biostudies-literature
Project description:The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of Parvalbumin- and Somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.
2024-06-05 | GSE263082 | GEO
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches.
2015-12-15 | GSE74065 | GEO
Project description:The functional output of the hippocampus, a brain region subserving memory processes, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular processes involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role in the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. We find that TIMP2 regulates accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in migration of newborn neurons through a denser ECM network. A conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.
2023-11-02 | GSE223188 | GEO
Project description:We used microarrays to assess gene expression differences in the hippocampus between FoxO6 mutant and wild-type siblings before (basal) or after novel object learning. The cohort of basal mice were housed individually for at least 3 days prior to tissue harvesting. The mice used to collect hippocampal samples after the object learning task were handled daily in the procedure room, prior to the object learning task. 24 hours before the object learning task, each mouse was individually habituated to the empty novel object arena for 10 min. On the days of the novel object learning task and the empty arena habituation, the mice were transferred to the procedure room and acclimatized for 60 min. For the novel object learning task, the mice were allowed to explore two identical and novel objects for 10 min in a 70 x 70 x 70 cm black plastic arena with a white PVC vinyl material on the base. After the object exploration, mice were transferred to an empty cage, and were euthanized after 60 min. The brains were dissected and incubated in ice-cold RNAlater (Ambion) for 24 hours at 4M-BM-:C. The brains were then rapidly frozen in O.C.T. Tissue-Tek (Sakura) at -80M-BM-:C. Coronal brain sections (300 M-BM-5m) were made using a microtome (Microm), the hippocampus was finely dissected and collected into M-bM-^@M-^XRNA lysis bufferM-bM-^@M-^Y (Ambion), and homogenized for 30 sec using a rotar-stat homogenizer. Total RNA was extracted using the RNAqueous column (Ambion) following the manufacturerM-bM-^@M-^Ys protocol.
2012-11-08 | E-GEOD-42097 | biostudies-arrayexpress
Project description:Dysregulation of the brain-enriched RNA binding protein Rbfox1 has been linked to neurologic diseases such as epilepsy and autism spectrum disorders. However, it remains unexplored how distinct neuronal populations might contribute to neurologic dysfunction resulting from Rbfox1 loss. To examine these issues we profiled gene expression specifically in the hippocampus of wildtype and Rbfox1-/- mice. We identified transcripts whose expression was strongly Rbfox1-dependent and exhibited significant Rbfox1 binding in their 3’UTRs. One prominent target, Vamp1, was found to be specifically expressed in GABAergic interneurons. Both Vamp1 knockdown and Rbfox1 loss led to decreased synaptic transmission, and altered E/I balance in the Rbfox1-/- hippocampus, indicating that Vamp1 loss is a major component of the Rbfox1-/- physiological phenotype. The cytoplasmic isoform of Rbfox1 was sufficient to rescue Vamp1 expression in Rbfox1-/- neurons. We show that Rbfox1 binding in the Vamp1 3’UTR promotes its expression in part by antagonizing the brain-enriched microRNA-9. These results demonstrate that inhibitory neurons maintain specialized synaptic vesicle release machinery containing Vamp1 that is critically regulated by Rbfox1.
2018-04-04 | GSE96722 | GEO
Project description:We sequenced six types of interneurons from adult mouse frontal cortex across multiple library batches to determine GABAergic neuronal identity
2017-09-22 | GSE92522 | GEO
Project description:Loss of the nuclear-encoded brain-specific arginine UCU tRNA, n-Tr20, gene increases seizure threshold in mice, and alters inhibitory neurotransmission in the hippocampus. We investigated the molecular impact of loss of n-Tr20 expression on the trancriptome and translatome in the forebrain and hippocampus of multiple n-Tr20 mutant and control strains. Loss of n-Tr20 altered translation initiation by activating the integrated stress response and suppressing mTOR signaling, the latter of which contributes to the enhanced GABAergic transmission.
2020-06-04 | GSE151742 | GEO