SPACE PROVIDED. Action potentials underlie fast electrical signaling between neurons in the mammalian central nervous system. Information is encoded in the shape, timing, and frequency of action potentials. The particular kinetic properties of sodium and potassium channels differ among neurons, and in addition to determining the shape of an action potential, the particular combination and kinetic properties of sodium and potassium channels can greatly influence the timing of subsequent action potentials and thus firing patterns. Calcium influx through voltage-gated calcium channels can help determine action potential shape and generation through its own depolarizing current as well as by catalyzing a host of intracellular signaling cascades. Cerebellar Purkinje neurons are an example of "fast-spiking" neurons, which can sustain steady firing rates of more than 300 Hz. The goal of this research is to understand how the kinetics of particular voltage-dependent ion channels determine the frequency of action potential generation in cerebellar Purkinje cells, especially in the limit of rapid firing. I will record action potential firing in current-clamp, and in the same cell, I will apply the recorded voltage trace as a command in voltage-clamp. Using this action potential-clamp method, I will study the macroscopic currents during action potential firing to answer three specific questions: (1) How does the availability of sodium channels during the firing cycle help determine the maximal possible firing frequency? (2) How and why are Kv3 family potassium channels required for high frequency firing? (3) How does calcium entry through voltage-gated calcium channels during an action potential regulate the pattern and frequency of action potential firing? Finally, I will examine other fast-spiking neurons to test the general applicability of my Purkinje cell results. Understanding the contribution of specific types and gating properties of ion channels in enabling high-frequency firing will give insight into normal and malfunctioning nervous systems and perhaps provide clues to treating disorders such as epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS064630-03
Application #
8010630
Study Section
Special Emphasis Panel (ZRG1-F03B-D (20))
Program Officer
Silberberg, Shai D
Project Start
2009-02-01
Project End
2011-08-31
Budget Start
2011-02-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$21,180
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115