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? subunit-containing GABA_A IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

ABSTRACT:

Key points

Current views suggest ?2 subunit-containing GABA_A 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.

Abstract

GABA_A 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 GABA_A receptors akin to that of slow NMDA and fast AMPA EPSCs at glutamate synapses.

SUBMITTER: Sun MY

PROVIDER: S-EPMC7071981 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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δ subunit-containing GABA<sub>A</sub> IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

Sun Min-Yu MY Ziolkowski Luke L Mennerick Steven S

The Journal of physiology 20200227 6

<h4>Key points</h4>Current views suggest γ2 subunit-containing GABA<sub>A</sub> receptors mediate phasic IPSCs while extrasynaptic δ 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 δ subunit. Using pharmacological separation, we find that in general δ and γ IPSCs are modulated in parallel by manipulations of transmitter output and diffusion, with evid ...[more]

PMID: 31951019

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Dataset Information

? subunit-containing GABA_A IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

Key points

Abstract

Publications

δ subunit-containing GABA<sub>A</sub> IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

? subunit-containing GABAA IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

Key points

Abstract

Publications

δ subunit-containing GABA<sub>A</sub> IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

? subunit-containing GABA_A IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.