Abstract
Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABAARs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABAAR-γ2subunits. Prevention of the CaN–GABAA receptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABAA receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.
