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

Christopher M Davenport; Rajit Rajappa; Ljudmila Katchan; Charlotte R Taylor; Ming-Chi Tsai; Caleb M Smith; Johannes W de Jong; Don B Arnold; Stephan Lammel; Richard H Kramer

doi:10.1016/j.neuron.2020.09.037

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

Neuron. 2021 Jan 6;109(1):123-134.e4. doi: 10.1016/j.neuron.2020.09.037. Epub 2020 Oct 22.

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, CA 90089, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rhkramer@berkeley.edu.

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.

Keywords: GABA receptors; LTP; learning; memory; metaplasticity; optogenetic pharmacology; synaptic plasticity; ɑ5-GABARs.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Excitatory Postsynaptic Potentials / physiology*
Female
Hippocampus / metabolism
Inhibitory Postsynaptic Potentials / physiology*
Male
Memory / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neuronal Plasticity / physiology*
Receptors, GABA-A / genetics
Receptors, GABA-A / metabolism*
Reversal Learning / physiology
Synapses / genetics
Synapses / metabolism*

Substances

Receptors, GABA-A