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Relocation of an Extrasynaptic GABA_A Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

ABSTRACT: The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of excitatory LTP. We developed a knockin mouse that allows optical control of endogenous α5-subunit-containing γ-aminobutyric acid (GABA)_A receptors (α5-GABARs). Induction of excitatory LTP relocates α5-GABARs, which are ordinarily extrasynaptic, to inhibitory synapses, quashing further NMDA receptor activation necessary for inducing more excitatory LTP. Blockade of α5-GABARs accelerates reversal learning, a behavioral test for cognitive flexibility dependent on repeated LTP. Hence, inhibitory synaptic plasticity occurs in parallel with excitatory synaptic plasticity, with the ensuing interruption of the positive feedback cycle of LTP serving as a possible critical early step in preserving memory.

SUBMITTER: Davenport CM

PROVIDER: S-EPMC7790995 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Relocation of an Extrasynaptic GABA<sub>A</sub> Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

Davenport Christopher M CM Rajappa Rajit R Katchan Ljudmila L Taylor Charlotte R CR Tsai Ming-Chi MC Smith Caleb M CM de Jong Johannes W JW Arnold Don B DB Lammel Stephan S Kramer Richard H RH

Neuron 20201022 1

The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of excitato ...[more]

PMID: 33096025

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Project description:BackgroundType 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABAARs) in pancreatic islets and the fact that GABAAR agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [11C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABAAR by unlabeled flumazenil. The pancreatic binding of [11C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABAAR subunits in pig, human and mouse pancreas was explored by immunohistochemistry.ResultsStrong specific in vivo uptake of [11C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [11C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABAAR subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing.ConclusionsOur findings suggest that [11C]FMZ bind to GABAARs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABAARs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABAAR could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABAAR subunits.

Dataset Information

Relocation of an Extrasynaptic GABA_A Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

Publications

Relocation of an Extrasynaptic GABA<sub>A</sub> Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

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Dataset Information

Relocation of an Extrasynaptic GABAA Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

Publications

Relocation of an Extrasynaptic GABA&lt;sub&gt;A&lt;/sub&gt; Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Relocation of an Extrasynaptic GABA_A Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.

Relocation of an Extrasynaptic GABA<sub>A</sub> Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory.