Role of the Cav3-Kv4 Complex in Cerebellar Granule Cells
Abstract
The cerebellum has a simple anatomy and a comparatively small number of neuronal classes connected by clearly defined excitatory and inhibitory projections. The cerebellum is thus an ideal area to study signal processing in neurons and how this behaviour contributes to overall circuit function. A key factor in how the postsynaptic machinery of a neuron converts the information it receives into an output is determined by their intrinsic level of excitability, which in turn determines the pattern or frequency of nerve impulse (spike) discharge. The intrinsic excitability of neurons is determined by the complement of ion channels expressed in the membrane. A low voltage-gated potassium channel of the Kv4 family that is important to regulating spike output in numerous CNS cells is highly expressed in granule cells. The Kv4 channels and low voltage-gated calcium channels of the Cav3 family are known to interact with each other in stellate cells of the cerebellum, whereby the influx of calcium ions enhances the efflux of potassium ions to reduce cell excitability. Thus, any change in the degree of this interaction can fine-tune the role of the Cav3-Kv4 complex in modifying membrane excitability and signal processing via Kv4 channels. This PhD project investigated the hypothesis that the differential expression of a Cav3-Kv4 channel complex and resulting Kv4 availability regulates granule cell excitability, spike output, and learning across the cerebellar lobules. This study used in vitro slices of rat cerebellum to conduct immunocytochemistry and electrophysiological voltage- and current-clamp recordings in the granule cells. Indeed, using immunocytochemistry, this study uncovered differential expression of the Cav3-Kv4 complex across the cerebellar lobules. The electrophysiology work also uncovered key differences in the postsynaptic expression and activity of the Cav3-Kv4 complex between anterior and posterior cerebellum that shapes the processing of mossy fibre input by granule cells. The synaptic plasticity data also revealed a novel NMDAR-mGluR-ERK-Kv4 interplay in cerebellar granule cells that functions to regulate postsynaptic excitability and synaptic responses to mossy fiber input. Overall, this study advances our understanding of the ionic mechanisms that underlie differential signal processing across cerebellar lobules.
Description
Keywords
Neuroscience
Citation
Rizwan, A. (2016). Role of the Cav3-Kv4 Complex in Cerebellar Granule Cells (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27686