Inhibition promotes long-Term potentiation at cerebellar excitatory synapses

Abstract

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 GABA A 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 GABA A 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.