The goal of the proposed research is to understand how the many types of ion channels present in a single neuron work together to produce the firing patterns typical of that neuron. Ultimately, we would like to use this knowledge to develop ion channel-targeted pharmacological agents able to differentially regulate firing of different types of neurons and thereby treat pathophysiological behavior such as epilepsy. In previous grant periods, we focused on the functional roles of voltage-dependent calcium channels and sodium channels. The focus in the next grant period is to understand how different potassium channels combine to regulate the firing patterns of specific types of neurons. We will follow up preliminary data showing that inhibition of Kv2, Kv3, and BK potassium channels often causes paradoxical slowing rather than speeding of firing. We will test two possible mechanisms for this effect: enhanced inactivation of Na channels or recruitment of other potassium channels with slower deactivation. An important element of the approach is to compare action potentials in different types of neurons. We will focus on three types of neurons chosen to be examples of major electrophysiological phenotypes: hippocampal CA1 pyramidal neurons, cerebellar Purkinje neurons, and midbrain dopamine neurons. The experimental design will combine current clamp recordings of action potential firing with voltage- clamp analysis of the underlying currents, using both intact neurons in brain slice and acutely dissociated neurons, which allow fast voltage clamp to study gating on the rapid time scale of the action potential. A key feature o the approach will be to study both action potential firing and channel gating kinetics at 37C. Current clamp and voltage clamp experiments will be directly linked by the action potential clamp technique, in which recordings of natural firing behavior are used as voltage clamp commands to allow pharmacological dissection of the components of current generating patterns of action potentials. The research will include substantial characterization of pharmacological agents to block potassium channel subtypes.

Public Health Relevance

Understanding the basic mechanisms that control the excitability of central neurons will help in understanding the normal function of the nervous system as well as pathophysiology resulting from epilepsy, Parkinson's disease, and other disorders. Characterization of blockers targeted to specific channels will provide useful tools for neuroscience research and may lead to new ways of controlling pathophysiology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Talley, Edmund M
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Harvard University
Schools of Medicine
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Liu, Pin W; Bean, Bruce P (2014) Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons. J Neurosci 34:4991-5002
Ellis, Samantha; Kalinowski, Danuta S; Leotta, Lisa et al. (2014) Potent antimycobacterial activity of the pyridoxal isonicotinoyl hydrazone analog 2-pyridylcarboxaldehyde isonicotinoyl hydrazone: a lipophilic transport vehicle for isonicotinic acid hydrazide. Mol Pharmacol 85:269-78
Kimm, Tilia; Bean, Bruce P (2014) Inhibition of A-type potassium current by the peptide toxin SNX-482. J Neurosci 34:9182-9
Jo, Sooyeon; Bean, Bruce P (2014) Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol 85:381-7
Yamada-Hanff, Jason; Bean, Bruce P (2013) Persistent sodium current drives conditional pacemaking in CA1 pyramidal neurons under muscarinic stimulation. J Neurosci 33:15011-21
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
Milescu, Lorin S; Bean, Bruce P; Smith, Jeffrey C (2010) Isolation of somatic Na+ currents by selective inactivation of axonal channels with a voltage prepulse. J Neurosci 30:7740-8
Khaliq, Zayd M; Bean, Bruce P (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30:7401-13
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
Khaliq, Zayd M; Bean, Bruce P (2008) Dynamic, nonlinear feedback regulation of slow pacemaking by A-type potassium current in ventral tegmental area neurons. J Neurosci 28:10905-17

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