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Physiological role for GABA_A receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

ABSTRACT: GABA_A receptors (GABA_ARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 h following desensitization of GABA_ARs in response to agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABA_ARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a physiological relevance to the desensitized state of GABA_ARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission.

SUBMITTER: Field M

PROVIDER: S-EPMC8035410 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

Field Martin M Dorovykh Valentina V Thomas Philip P Smart Trevor G TG

Nature communications 20210409 1

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here ...[more]

PMID: 33837214

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Project description:Long-term potentiation (LTP) is an activity-dependent and persistent increase in synaptic transmission. Currently available techniques to measure LTP are time-intensive and require highly specialized expertise and equipment, and thus are not well suited for screening of multiple candidate treatments, even in animal models. To expand and facilitate the analysis of LTP, here we use a flow cytometry-based method to track chemically induced LTP by detecting surface AMPA receptors in isolated synaptosomes: fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). First, we demonstrate that FASS-LTP is simple, sensitive, and models electrically induced LTP recorded in intact circuitries. Second, we conducted FASS-LTP analysis in two well-characterized Alzheimer's disease (AD) mouse models (3xTg and Tg2576) and, importantly, in cryopreserved human AD brain samples. By profiling hundreds of synaptosomes, our data provide the first direct evidence to support the idea that synapses from AD brain are intrinsically defective in LTP. Third, we used FASS-LTP for drug evaluation in human synaptosomes. Testing a panel of modulators of cAMP and cGMP signaling pathways, FASS-LTP identified vardenafil and Bay-73-6691 (phosphodiesterase-5 and -9 inhibitors, respectively) as potent enhancers of LTP in synaptosomes from AD cases. These results indicate that our approach could provide the basis for protocols to study LTP in both healthy and diseased human brains, a previously unattainable goal.Significance statementLearning and memory depend on the ability of synapses to strengthen in response to activity. Long-term potentiation (LTP) is a rapid and persistent increase in synaptic transmission that is thought to be affected in Alzheimer's disease (AD). However, direct evidence of LTP deficits in human AD brain has been elusive, primarily due to methodological limitations. Here, we analyze LTP in isolated synapses from AD brain using a novel approach that allows testing LTP in cryopreserved brain. Our analysis of hundreds of synapses supports the idea that AD-diseased synapses are intrinsically defective in LTP. Further, we identified pharmacological agents that rescue LTP in AD, thus opening up a new avenue for drug screening and evaluation of strategies for alleviating memory impairments.

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Physiological role for GABA_A receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

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Physiological role for GABA<sub>A</sub> receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

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Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

Publications

Physiological role for GABA&lt;sub&gt;A&lt;/sub&gt; receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

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OmicsDI is part of the ELIXIR infrastructure

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Physiological role for GABA_A receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

Physiological role for GABA<sub>A</sub> receptor desensitization in the induction of long-term potentiation at inhibitory synapses.