Dataset Information

Genetic Deletion of GABA_A Receptors Reveals Distinct Requirements of Neurotransmitter Receptors for GABAergic and Glutamatergic Synapse Development.

ABSTRACT: In the adult brain GABA_A receptors (GABA_ARs) mediate the majority of synaptic inhibition that provides inhibitory balance to excitatory drive and controls neuronal output. In the immature brain GABA_AR signaling is critical for neuronal development. However, the cell-autonomous role of GABA_ARs in synapse development remains largely unknown. We have employed the CRISPR-CAS9 technology to genetically eliminate GABA_ARs in individual hippocampal neurons and examined GABAergic and glutamatergic synapses. We found that development of GABAergic synapses, but not glutamatergic synapses, critically depends on GABA_ARs. By combining different genetic approaches, we have also removed GABA_ARs and two ionotropic glutamate receptors, AMPA receptors (AMPARs) and NMDA receptors (NMDARs), in single neurons and discovered a striking dichotomy. Indeed, while development of glutamatergic synapses and spines does not require signaling mediated by these receptors, inhibitory synapse formation is crucially dependent on them. Our data reveal a critical cell-autonomous role of GABA_ARs in inhibitory synaptogenesis and demonstrate distinct molecular mechanisms for development of inhibitory and excitatory synapses.

SUBMITTER: Duan J

PROVIDER: S-EPMC6558517 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genetic Deletion of GABAA Receptors Reveals Distinct Requirements of Neurotransmitter Receptors for GABAergic and Glutamatergic Synapse Development.

Duan Jingjing J Pandey Saurabh S Li Tianming T Castellano David D Gu Xinglong X Li Jun J Tian Qingjun Q Lu Wei W

Frontiers in cellular neuroscience 20190604

In the adult brain GABAA receptors (GABAARs) mediate the majority of synaptic inhibition that provides inhibitory balance to excitatory drive and controls neuronal output. In the immature brain GABAAR signaling is critical for neuronal development. However, the cell-autonomous role of GABAARs in synapse development remains largely unknown. We have employed the CRISPR-CAS9 technology to genetically eliminate GABAARs in individual hippocampal ...[more]

PMID: 31231192

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Project description: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.

Dataset Information

Genetic Deletion of GABA_A Receptors Reveals Distinct Requirements of Neurotransmitter Receptors for GABAergic and Glutamatergic Synapse Development.

Publications

Genetic Deletion of GABA<sub>A</sub> Receptors Reveals Distinct Requirements of Neurotransmitter Receptors for GABAergic and Glutamatergic Synapse Development.

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