The Expression Pattern of a Cav3-Kv4 Complex Differentially Regulates Spike Output in Cerebellar Granule Cells

Abstract

The cerebellum receives sensory information by mossy fiber input from a multitude of sources that require differential signal processing. A compartmentalization of function begins with the segregation of mossy fibers across 10 distinct lobules over the rostrocaudal axis, with tactile receptor afferents prevalent in anterior lobules and vestibular input in caudal lobules. However, it is unclear how these unique signals might be differentially processed at the circuit level across the cerebellum. As granule cells receive mossy fiber input, they represent a key stage at which postsynaptic mechanisms could influence signal processing. Granule cells express an A-type current mediated by Kv4 potassium channels that modify the latency and frequency of spike output. The current study examined the potential for a Cav3 calcium-Kv4 channel complex to regulate the response of granule cells to mossy fiber input in lobules 2 and 9 of the rat cerebellum. Similar A-type currents were recorded in both regions, but the Cav3 calcium current was expressed at a substantially higher density in lobule 9 cells, acting to increase A-type current availability through its influence on Kv4 voltage for inactivation. The difference in excitability imparted by Cav3-Kv4 interactions proves to allow lobule 2 granule cells to respond more effectively to tactile stimulus-like burst input and lobule 9 cells to slow shifts in input frequency characteristic of vestibular input. The expression pattern of Cav3 channels and its control of Kv4 availability thus provides a novel means of processing widely different forms of sensory input across cerebellar lobules.

Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating

“…In cerebellar granule cells, for example, synaptic inputs from mossy fibers may induce hyperpolarizing shifts in both half‐activation and half‐inactivation voltages of K V 4 channels, thereby invoking long‐term increase in granule cell excitability (Rizwan, Zhan, Zamponi, & Turner, ). Furthermore, in cerebellar granule and stellate cells, T‐type Ca 2+ (Ca V 3) channels form a signaling complex with K V 4 and the Ca 2+ ‐sensing KChIP, whereby Ca V 3‐mediated Ca 2+ influx significantly enhances I SA by causing depolarizing shift of K V 4 half‐inactivation voltage (Anderson et al, ; Heath et al, ; Molineux, Fernandez, Mehaffey, & Turner, ). The physiological significance of this Ca V 3‐K V 4 signaling complex is further underlined by the findings that Ca V 3 current density critically determines regional differences in membrane excitability and spike output of granule cells (Heath et al, ), and that extracellular Ca 2+ may regulate inhibitory outputs from stellate cells to cerebellar Purkinje cells (Anderson et al, ).…”

“…Furthermore, in cerebellar granule and stellate cells, T‐type Ca 2+ (Ca V 3) channels form a signaling complex with K V 4 and the Ca 2+ ‐sensing KChIP, whereby Ca V 3‐mediated Ca 2+ influx significantly enhances I SA by causing depolarizing shift of K V 4 half‐inactivation voltage (Anderson et al, ; Heath et al, ; Molineux, Fernandez, Mehaffey, & Turner, ). The physiological significance of this Ca V 3‐K V 4 signaling complex is further underlined by the findings that Ca V 3 current density critically determines regional differences in membrane excitability and spike output of granule cells (Heath et al, ), and that extracellular Ca 2+ may regulate inhibitory outputs from stellate cells to cerebellar Purkinje cells (Anderson et al, ). Consequently, it is likely that dominant‐negative effects of SCA19/22‐associated mutants on voltage‐dependent gating of K V 4.3 WT may similarly result in aberrant network excitability in the cerebellar circuits, which may in part manifest some of the ataxic features observed in the patients.…”

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

“…Thus, it is highly likely that Cav3 channels represent the physiological source of Ca 2+ for an acute gating modulation of membrane-bound Kv4.2/KChIP3 channels. In fact, Heath and coworkers [91] found out that regional differences in Cav3 channel expression directly correlated with the voltage-dependent I SA availability, and blocking Ca 2+ currents abolished regional differences in I SA density. The novel form of subcellular Ca 2+ signaling occurs within a protein complex, and the radius of action actually represents a Ca 2+ nanodomain (distance < 50 nm) [14,90].…”

Purkinje Cells Directly Inhibit Granule Cells in Specialized Regions of the Cerebellar Cortex

“…Cerebellar dysfunction results in ataxia and dystonia, and more recently has been implicated in autism spectrum disorder (Fatemi et al, 2012; Wang et al, 2014). A single canonical circuit is thought to underlie all cerebellar computations (Eccles et al, 1967; Schmahmann, 2004), although regional differences have been observed (Cerminara et al, 2015; Dino et al, 1999; Heath et al, 2014; Witter and De Zeeuw, 2015). …”