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

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. [Display omitted] •Optical control of endogenous GABAA receptors containing the ɑ5 subunit•Excitatory activity redistributes extrasynaptic ɑ5-GABARs to inhibitory synapses•ɑ5-GABARs prevent runaway hippocampal excitatory LTP•ɑ5-GABARs preserve learned associations in mice Long-term potentiation (LTP) of excitatory synaptic transmission strengthens neural circuit connections during learning. Davenport, Rajappa et al. show with optogenetic pharmacology that a specific receptor for the neurotransmitter GABA redistributes to inhibitory synapses, prolonging synaptic inhibition. This breaks the positive feedback of excitatory LTP to freeze synaptic strength and preserve memory.