TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

Abstract

23Despite the canonical homogenous character of its organization, the cerebellum plays 24 differential computational roles in distinct types of sensorimotor behaviors. However, the 25 molecular and cell physiological underpinnings are unclear. Here we determined the 26 contribution of transient receptor potential cation channel type C3 (TRPC3) to signal 27 processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse 28 models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z-), but 29 not of zebrin-positive (Z+), Purkinje cells. Moreover, in vivo TRPC3 also regulated complex 30 spike firing and its interaction with simple spikes exclusively in Z-Purkinje cells. Finally, we 31 found that eyeblink conditioning, related to Z-modules, but not compensatory eye movement 32 adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our 33 results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct 34 physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring 35 functional heterogeneity in cerebellar sensorimotor integration. 36 37Recently, it has been uncovered that the sole output neurons of the cerebellar cortex, the 47 Purkinje cells (PCs), can be divided into two main groups with a distinct firing behavior 10,11 . 48 One group, consisting of PCs that are positive for the glycolytic enzyme aldolase C, also 49 referred to as zebrin II 12,13 , shows relatively low simple spike firing rates, whereas the PCs in 50 the other group that form zebrin-negative zones, fire at higher rates 10 . Zebrin II demarcates 51 olivocerebellar modules, anatomically defined operational units each consisting of a closed 52 loop between the inferior olive, parasagittal bands of the cerebellar cortex and the cerebellar 53 nuclei 14,15 . Given that different motor domains are controlled by specific olivocerebellar 54 modules 14,16 , the differential intrinsic firing frequencies may be tuned to the specific neuronal 55 demands downstream of the cerebellum 17 . Thus, dependent on the specific behavior 56 controlled by the module involved, the PCs engaged may show low or high intrinsic firing as 57 well as related plasticity rules to adjust these behaviors. 58Cellular heterogeneity can drive differentiation in the activity and plasticity of individual 59 cells that operate within a larger ensemble 18 . The molecular and cellular determinants of 60 differential electrophysiological processing in the cerebellar PC modules are just starting to be 61 identified 19,20 . For example, while the impact of zebrin II itself is still unclear 10 , excitatory 62 amino acid transporter 4 (EAAT4) and GLAST/EAAT1 can directly modulate simple spike 63 activity of PCs as well as plasticity of their parallel fiber inputs in a zone specific manner 21,22 . 64 4 Likewise, phospholipase C subtype β4 (PLCβ4) is required for climbing fiber elimination and 65 PF-PC LTD through mGluR1 activation by spi...