Revealing ‘the other kind of LTP’ in cerebellar interneurons
Ryan Alexander (Post-Doctoral Fellow)
Laboratory of Derek Bowie. McGill University, Canada
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Memory storage in the mammalian brain is mediated not only by long-lasting changes in the efficacy of neurotransmitter receptors but also by long-term modifications to the activity of voltage-gated ion channels. Activity-dependent plasticity of voltage-gated ion channels, or intrinsic plasticity, is found throughout the brain in virtually all neuronal types including principal cells and interneurons. Although originally observed in the cerebellum, intrinsic plasticity has yet to be studied in GABAergic molecular layer interneurons (MLIs) which regulate cerebellar cortical output via feedforward inhibition onto Purkinje cells. The study of long-term excitability regulation in MLIs has been particularly challenging as membrane patch breakthrough in electrophysiology experiments unintentionally triggers changes in spontaneous firing rates. Using cell-attached patch recordings to avoid disruption, we show that activation of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) elicits a long-term increase in the firing properties of MLIs by stimulating a rise in cytosolic Ca2+ and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). An identical signaling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of voltage-gated sodium (Nav) channels. Together, our findings identify an unappreciated role of Nav channel-dependent intrinsic plasticity in cerebellar MLIs which, in concert with non-canonical NMDAR signaling, provides the cerebellum with an unconventional mechanism to fine-tune motor behavior.