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
Womack M D, and Khodakhah K (2004). Dendritic Control of Spontaneous Bursting in Cerebellar Purkinje Cells. J. Neurosci. 7;24(14):3511-21.
Morikawa H, Khodakhah K, Williams J T (2003).Two intracellular pathways mediate metabotropic glutamate receptor-induced Ca2+ mobilization in dopamine neurons. J Neurosci. 1;23(1):149-57
.
Womack M D, and Khodakhah K (2003). Somatic and Dendritic Small-Conductance Calcium-Activated Potassium Channels Regulate the Output of Cerebellar Purkinje Neurons. J. Neurosci. 23: 2600-2607.
Womack M D, Khodakhah K (2002). Characterization
of large conductance Ca2+-activated K+ channels in
cerebellar Purkinje neurons. Eur J Neurosci. 6(7):1214-22.
Womack M D, and Khodakhah K (2002). Active
contribution of dendrites to the tonic and trimodal
patterns of activity in cerebellar Purkinje neurons. J Neurosci. 15;22(24):10603-10612.
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