Priming of GABAergic Long-term Potentiation by Muscarinic Receptors

Growing evidence indicates that GABAergic interneurons play a pivotal role to generate brain oscillation patterns, which are fundamental for the mnemonic processing of the hippocampus. While acetylcholine (ACh) is a powerful modulator of synaptic plasticity and brain function, few studies have been focused on the role of cholinergic signaling in the regulation of GABAergic inhibitory synaptic plasticity. We have previously shown that co-activation of endocannabinoids (CB1R) and muscarinic receptor (mAChR) in hippocampal interneurons can induce activity-dependent GABAergic long-term depression in CA1 pyramidal neurons. Here, using electrophysiological and pharmacological approaches in acute rat hippocampal slices, we show that activation of cholinergic receptors followed by either high-frequency stimulation of Schaeffer collaterals or exogenous activation of metabotropic glutamate receptor (mGluR) induces a robust long-term potentiation at GABAergic synapses (iLTP). These forms of iLTP are blocked by the M1 type of mAChR (MR1) or by the group I of mGluR (mGluR1/5) antagonists. These results suggest the existence of spatiotemporal cooperativity between cholinergic and glutamatergic pathways where activation of mAChR serves as a metaplastic switch making glutamatergic synapses capable to induce long-term potentiation at inhibitory synapses, that may contribute to the modulation of brain mechanisms of learning and memory.