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 alpha 5-subunit-containing gamma-aminobutyric acid (GABA)(A) receptors (alpha 5-GABARs). Induction of excitatory LTP relocates alpha 5-GABARs, which are ordinarily extrasynaptic, to inhibitory synapses, quashing further NMDA receptor activation necessary for inducing more excitatory LTP. Blockade of alpha 5-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.

Automated summary

The study uncovers a hidden form of inhibitory synaptic plasticity that prevents the accumulation of excitatory long-term potentiation (LTP). Induction of excitatory LTP relocates α5-GABARs to inhibitory synapses, interrupting further LTP induction. This dual plasticity between inhibitory and excitatory synapses may be a critical early step in memory preservation.