Dataset Information

Cerebellum-Specific Deletion of the GABA_A Receptor ? Subunit Leads to Sex-Specific Disruption of Behavior.

ABSTRACT: Granule cells (GCs) of the cerebellar input layer express high-affinity ? GABA_A subunit-containing GABA_A receptors (?GABA_ARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of ?GABA_A (cerebellar [cb] ? knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb ? KO mice display deficits in many behaviors, but motor function is normal. Strikingly, ?GABA_A deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that ?GABA_ARs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias.

SUBMITTER: Rudolph S

PROVIDER: S-EPMC7700496 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior.

Rudolph Stephanie S Guo Chong C Pashkovski Stan L SL Osorno Tomas T Gillis Winthrop F WF Krauss Jeremy M JM Nyitrai Hajnalka H Flaquer Isabella I El-Rifai Mahmoud M Datta Sandeep Robert SR Regehr Wade G WG

Cell reports 20201101 5

Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABAA subunit-containing GABAA receptors (δGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABAA (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical b ...[more]

PMID: 33147470

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Project description:Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "?5-PAM"), a positive allosteric modulator selective for ?5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with ?5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic ?5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic ?5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to ?5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with ?5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of ?5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

Project description:Key pointsCurrent views suggest ?2 subunit-containing GABAA receptors mediate phasic IPSCs while extrasynaptic ? subunits mediate diffusional IPSCs and tonic current. We have re-examined the roles of the two receptor populations using mice with picrotoxin resistance engineered into receptors containing the ? subunit. Using pharmacological separation, we find that in general ? and ? IPSCs are modulated in parallel by manipulations of transmitter output and diffusion, with evidence favouring modestly more diffusional contribution to ? IPSCs. Our findings also reveal that spontaneous ? IPSCs are mainly driven by channel deactivation, rather than by diffusion of GABA. Understanding the functional contributions of the two receptor classes may help us understand the actions of drug therapies with selective effects on one population over the other.AbstractGABAA receptors mediate transmission throughout the central nervous system and typically contain a ? subunit (? receptors) or a ?2 subunit (?2 receptors). ? IPSCs decay slower than ?2 IPSCs, but the reasons are unclear. Transmitter diffusion, rebinding, or slow deactivation kinetics of channels are candidates. We used gene editing to confer picrotoxin resistance on ? receptors in mice, then pharmacologically isolated ? receptors in mouse dentate granule cells to explore IPSCs. ?2 and ? components of IPSCs were modulated similarly by presynaptic manipulations and manipulations of transmitter lifetime, suggesting that GABA release recruits ? receptors proportionally to ?2 receptors. ? IPSCs showed more sensitivity to altered transmitter release and to a rapidly dissociating antagonist, suggesting an additional spillover contribution. Reducing GABA diffusion with 5% dextran increased the peak amplitude and decreased the decay of evoked ? IPSCs but had no effect on ? or dual-component (mainly ?2-driven) spontaneous IPSCs, suggesting that GABA actions can be local for both receptor types. Rapid application of varied [GABA] onto nucleated patches from dentate granule cells demonstrated a deactivation rate of ? receptors similar to that of ? spontaneous IPSCs, consistent with the idea that deactivation and local GABA actions drive ? spontaneous IPSCs. Overall, our results indicate that ? IPSCs are activated by both synaptic and diffusional GABA. Our results are consistent with a functional relationship between ? and ?2 GABAA receptors akin to that of slow NMDA and fast AMPA EPSCs at glutamate synapses.

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Cerebellum-Specific Deletion of the GABA_A Receptor ? Subunit Leads to Sex-Specific Disruption of Behavior.

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Cerebellum-Specific Deletion of the GABA<sub>A</sub> Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior.

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Cerebellum-Specific Deletion of the GABAA Receptor ? Subunit Leads to Sex-Specific Disruption of Behavior.

Publications

Cerebellum-Specific Deletion of the GABA<sub>A</sub> Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Cerebellum-Specific Deletion of the GABA_A Receptor ? Subunit Leads to Sex-Specific Disruption of Behavior.