ELECTROPHYSIOLOGICAL CHARACTERIZATION OF DYSFUNCTION IN PURKINJE NEURONS IN A NEW MOUSE MODEL FOR CHILDHOOD-ONSET CEREBELLAR ATROPHY

A de novo gain-of-function mutation (p.A961T) in the Ca_v3.1 channels has been linked to childhood-onset cerebellar atrophy (SCA42ND) with profound motor and cognitive impairment. Ca_v3.1 is abundantly expressed in the Purkinje Cells (PCs) dendrites and spines, which are the primary computational units of the cerebellum. Previous studies have shown that Ca_v3.1 are low-voltage activated channels, that are required for parallel fiber (PF)-PC long term potentiation via coupling with mGluR1 receptors. To understand how the mutation affects the cerebellar function, a mouse model with conditional (floxed) Ca_v3.1 (A961T) knock-in has been generated. The mutation was expressed selectively in PCs using pcp2(L7)-Cre, and electrophysiological recordings were performed in acute cerebellar slices. We observed a reduction of PC firing rates in the anterior lobules (I and II) in the mutants, while firing rates remain comparable to the control in the posterior lobules (IX and X). Using current-clamp recordings, an increase in the rebound after hyperpolarization was observed, in agreement with the gain-of-function hypothesis. We are now developing 2-photon calcium imaging combined with PF stimulation to study calcium signaling in dendritic spines. We think this model captures the electrophysiological signature of the gain-of-function mutation in Ca_v3.1 suggesting that this new mouse line could be a relevant model to study childhood-onset cerebellar atrophy.