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.
|Carter, Brett C; Giessel, Andrew J; Sabatini, Bernardo L et al. (2012) Transient sodium current at subthreshold voltages: activation by EPSP waveforms. Neuron 75:1081-93|
|Carter, Brett C; Bean, Bruce P (2011) Incomplete inactivation and rapid recovery of voltage-dependent sodium channels during high-frequency firing in cerebellar Purkinje neurons. J Neurophysiol 105:860-71|
|Carter, Brett C; Bean, Bruce P (2009) Sodium entry during action potentials of mammalian neurons: incomplete inactivation and reduced metabolic efficiency in fast-spiking neurons. Neuron 64:898-909|