Kamran Khodakhah

The Regulation of Neuronal Excitability and Synaptic Plasticity by Calcium Release

The ultimate goal of our laboratory is to understand how the cerebellum coordinates movement, and how its malfunction in disease causes ataxia and dystonia. We focus mainly on delineating the role and function of Purkinje cells within the cerebellum.

We are fortunate that the circuitry of the cerebellum is well understood. Purkinje cells are the sole output of the computational circuitry of the cerebellar cortex. These spontaneously active cells encode the timing signals required for motor coordination in their rate and pattern of activity. In the laboratory our efforts are focused in two areas: 1) understanding the mechanisms that give rise to, and regulate, the intrinsic spontaneous activity of Purkinje cells and 2) elucidating the role of synaptic transmission is shaping the output of Purkinje cells.

Using a combination of electrophysiological (single channel, whole cell patch clamp, and extracellular field potential recordings), and optical (calcium imaging using fast photomultipliers and CCD cameras, two photon microscopy, and flash photolysis) techniques, we have taken steps to tease out the function of individual ion channels, and the role of calcium in regulating the intrinsic excitability of Purkinje cells. Our studies on the mechanisms of regulation of intrinsic excitability in Purkinje cells have provided plausible explanations as to why mutations in certain ion channels cause ataxia in several human hereditary ataxia diseases. To compliment our studies, we often take advantage of transgenic and mutant mice as animal models of human hereditary ataxias.

We also study how Purkinje cells integrate synaptic input. Specifically, we use electrical stimulation of synaptic inputs or localized flash photolytic release of glutamate to delineate how Purkinje cells integrate excitatory and inhibitory synaptic information to formulate their output. We are also interested in defining the role of dendrites, and dendritic conductances, in synaptic integration in Purkinje cells.

By elucidating the cellular and synaptic mechanisms of cerebellar function we hope to not only better understand the role of cerebellum in motor coordination, but also to provide potential therapeutic targets in cerebellar diseases.

Selected Publications