Grant: Operating Grant

The brain is able to process information because ion channels that drive electrical activity provide the means for cells to communicate. All communication takes place at synaptic junctions, where ion channels can modulate incoming signals. This research project will examine signal processing in the cerebellum, a brain region critical to both motor control and cognitive (mental) functions. The cerebellum has an input layer of granule cells that receive mossy fiber input, a molecular layer for processing signals, and an output layer of Purkinje cells, all of which are folded into 10 different lobules over the rostro-caudal axis. Despite work performed to date, the functional roles of different lobules has remained an enigma. However, fMRI studies now show that cerebellar function is divided into motor control in rostral lobules and cognitive function in caudal lobules. In the past grant period we uncovered a novel complex between ion channels that generate calcium influx and potassium efflux (termed the Cav3-Kv4 complex). We found that these channels work in tandem, such that Cav3 calcium influx enhances Kv4 potassium efflux, allowing control over the excitability and timing of electrical impulses in neurons. We now find that the Cav3-Kv4 complex is expressed in granule cells, providing the means to shape signal processing at the first stage of cerebellar circuitry. Moreover, the expression pattern of Cav3 and Kv4 channels changes across lobules, leading to: Hypothesis - Cerebellar granule cell excitability and response to mossy fiber input is differentially regulated across cerebellar lobules by the expression pattern of the Cav3-Kv4 channel complex. This work will be important to understanding how sensory inputs carrying different forms of information are differentially processed across the multiple lobules of cerebellum, potentially identifying synaptic mechanisms that can be targeted for intervention in disorders of cerebellar function.