He, Q.; (2009) Rebound potential: long-term potential of inhibitory transmission at cerebellar interneuron-Purkinje cell synapses. Doctoral thesis , UCL (University College London).

Abstract

The cerebellum is vitally important for motor learning and this behaviour is heavily reliant on the plasticity of excitatory and inhibitory synaptic transmission. Over the past two decades, numerous forms of synaptic plasticity within the cerebellum have been described, particularly affecting the principle output inhibitory neuron, the Purkinje cell (PC). In this study, I have focused on the mechanism underlying the phenomenon of rebound potentiation (RP), which is a long-lasting enhancement of inhibitory transmission at interneuron-PC synapses. RP is triggered by strong climbing fibre induced depolarization of postsynaptic PCs. Subsequent Ca^{2+} influx via voltage-dependent calcium channels, and Ca^{2+} release from intracellular stores, synergise to activate Ca^{2+} dependent kinase pathways resulting in a persistent enhancement of synaptic γ aminobutryic acid type-A receptor (GABA_AR) mediated current on PCs. The types of RP that are induced can be classified as early and late RP. The induction of RP critically depends on both Ca^{2+}/Calmodulin-dependent protein kinase II (CaMKII) and protein tyrosine kinase (PTK) activation, as selective inhibitors (CaMKIINtide and genistein) blocked the RP of miniature inhibitory postsynaptic currents (mIPSCs). These kinases were found to work through inter-dependent pathways with PTK acting dowmtream of CaMKII. Furthermore, CaMKII activity is required for both the induction and the maintenance of RP. In PCs, the majority of GABA_ARs are comprised of α1β2γ2 subunits. The α1 subunit was essential for mediating the phasic inhibition observed in PCs; whereas, the β2 subunit-containing receptors underlied the large amplitude, fast rise time mIPSCs and were also critically important for the induction of RP. Thirdly, tyrosine phosphorylation of the γ2 subunit was found to determine the direction of plasticity, converting RP to a new phenomenon of rebound depression. Finally, by using inhibitors of SNARE-based exocytosis pathways, we determined that GABA_A receptor insertion is the underlying mechanism of RP. In conclusion, RP is a phosphorylation-dependent subunit-specific plasticity of GABA_ARs, which is manifest by postsynaptic GABA_A receptor insertion. As such, it may be an important contributory factor to motor learning in the cerebellum.

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