Expression and distribution of voltage-gated sodium channels in the cerebellum

Abstract

In order to understand the effects of sodium channels on synaptic signaling and response in the cerebellum, it is essential to know for each class of neuron what sodium channel isoforms are present, and the properties and distribution of each. Sodium channels are heteromultimeric membrane proteins, consisting of a large alpha subunit that forms the pore, and one or more beta subunits. Ten genes encode an alpha subunit in mammals, and of these, four are expressed in the cerebellum: Nav1.1, Nav1.2, Nav1.3 and Nav1.6. Three genes encode beta subunits (Nabeta1-3), and all three are expressed in the cerebellum. However, Nav1.3 and Nabeta3 have been found only in the developing cerebellum. All sodium channels recorded in the cerebellum are TTX-sensitive with similar kinetics, making it difficult to identify the isoforms electrically. Thus, most of the expression studies have relied on techniques that allow visualization of sodium channel subtypes at the level of mRNA and protein. In situ hybridization and immunolocalization studies demonstrated that granule cells predominantly express Nav1.2, Nav1.6, Nabeta1, and Nabeta2. Protein for Nav1.2 and Nav1.6 is localized primarily in granule cell parallel fibers. Purkinje cells express Nav1.1, Nav1.6, Nabeta1 and Nabeta2. The somato-dendritic localization of Nav1.1 and Nav1.6 in Purkinje cells suggests that these isoforms are involved in the integration of synaptic input. Deep cerebellar nuclei neurons expressed Nav1.1 and Nav1.6 as well as Nabeta1. Bergmann glia expressed Nav1.6, but not granule cell layer astrocytes. Some sodium channel isoforms that are not expressed normally in the adult cerebellum are expressed in animals with mutations or disease. Electrophysiological studies suggest that Nav1.6 is responsible for spontaneous firing and bursting features in Purkinje cells, but the specialized functions of the other subunits in the cerebellum remain unknown.