Inhibition promotes long-term potentiation at cerebellar excitatory synapses

The ability of the cerebellar cortex to learn from experience ensures the accuracy of movements and reflex adaptation, processes which require long-term plasticity at granule cell (GC) to Purkinje neuron (PN) excitatory synapses. PNs also receive GABAergic inhibitory inputs via GCs activation of interneurons; despite the involvement of inhibition in motor learning, its role in long-term plasticity is poorly characterized. Here we reveal a functional coupling between ionotropic GABAA receptors and low threshold Ca(V)3 calcium channels in PNs that sustains calcium influx and promotes long-term potentiation (LTP) at GC to PN synapses. High frequency stimulation induces LTP at GC to PN synapses and Ca(V)3-mediated calcium influx provided that inhibition is intact; LTP is mGluR1, intracellular calcium store and Ca(V)3 dependent. LTP is impaired in Ca(V)3.1 knockout mice but it is nevertheless recovered by strengthening inhibitory transmission onto PNs; promoting a stronger hyperpolarization via GABAA receptor activation leads to an enhanced availability of an alternative Purkinje-expressed Ca(V)3 isoform compensating for the lack of Ca(V)3.1 and restoring LTP. Accordingly, a stronger hyperpolarization also restores Ca(V)3-mediated calcium influx in PNs from Ca(V)3.1 knockout mice. We conclude that by favoring Ca(V)3 channels availability inhibition promotes LTP at cerebellar excitatory synapses.