α2δ-2 is Required for Depolarization-induced Suppression of Excitation in Purkinje cells

Abstract

2{delta} proteins (CACNA2D1-4) are required for normal neurological function, although how they control neuronal output remains unclear. Using whole-cell recordings of mouse Purkinje cells, we show 2{delta}-2 is required for functional coupling of postsynaptic voltage-dependent calcium entry with effector mechanisms controlling two different outputs, depolarization-induced suppression of excitation mediated by endocannabinoid signaling, and spike afterhyperpolarization generated by calcium-dependent potassium channels. Our findings indicate an important role for 2{delta}-2 proteins in regulating functional postsynaptic calcium channel-coupling in neurons. Significance StatementCalcium influx via membrane voltage-dependent calcium channels drives numerous neuronal processes by signaling through calcium-dependent effector molecules. Signal precision is achieved in part by calcium channel-effector coupling. In mouse Purkinje cell neurons, we show that neuronal 2{delta}-2 protein functionally couples calcium entry to two different postsynaptic calcium-dependent signals, retrograde endocannabinoid signaling and the action potential afterhyperpolarization. Our findings provide new insights about the control of calcium channel-effector coupling as well as new roles for 2{delta}-2 proteins in neurons.