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 GABAA receptors and low threshold CaV3 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 CaV3-mediated calcium influx provided that inhibition is intact; LTP is mGluR1, intracellular calcium store and CaV3 dependent. LTP is impaired in CaV3.1 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 CaV3 isoform compensating for the lack of CaV3.1 and restoring LTP. Accordingly, a stronger hyperpolarization also restores CaV3-mediated calcium influx in PNs from CaV3.1 knockout mice. We conclude that by favoring CaV3 channels availability inhibition promotes LTP at cerebellar excitatory synapses.
Highlights
Modulated by activation of the ionotropic GABAA receptor in vivo[18]
By investigating the molecular pathway leading to LTP in Purkinje neurons (PNs), we demonstrate a tight cooperation between ionotropic GABA receptors and low threshold voltage-gated T-type calcium channels (CaV3) which promotes LTP at parallel fibers (PFs) to PN synapses
PFs were stimulated at high frequency while PNs were switched to current clamp mode
Summary
Modulated by activation of the ionotropic GABAA receptor in vivo[18]. PNs express low threshold voltage-gated T-type calcium channels (CaV3) which have been recently linked to calcium signaling, LTP at PF to PN synapses and to some aspects of motor learning[15,20,21]. Recovery from inactivation requires cell membrane re-hyperpolarization and CaV3 channels can be influenced by inhibitory inputs as shown in thalamic neurons where GABAergic transmission promotes T-type channels-mediated low threshold calcium spikes[23,24]. By investigating the molecular pathway leading to LTP in PNs, we demonstrate a tight cooperation between ionotropic GABA receptors and low threshold voltage-gated T-type calcium channels (CaV3) which promotes LTP at PF to PN synapses. We conclude that FFI can control LTP at PF to PN synapses
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