An activity-dependent change in synaptic efficacy is a central tenet in learning, memory, and pathological states of neuronal excitability. The lateral diffusion dynamics of neurotransmitter receptors are one of the important parameters regulating synaptic efficacy. We report here that neuronal activity modifies diffusion properties of type-A GABA receptors (GABAAR) in cultured hippocampal neurons: enhanced excitatory synaptic activity decreases the cluster size of GABAARs and reduces GABAergic mIPSC. Single-particle tracking of the GABAAR γ2 subunit labeled with quantum dots reveals that the diffusion coefficient and the synaptic confinement domain size of GABAAR increases in parallel with neuronal activity, depending on Ca2+ influx and calcineurin activity. These results indicate that GABAAR diffusion dynamics are directly linked to rapid and plastic modifications of inhibitory synaptic transmission in response to changes in intracellular Ca2+ concentration. This transient activity-dependent reduction of inhibition would favor the onset of LTP during conditioning.
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