Work over the last twenty years has identified a remarkable number of proteins that form ion channels in the mammalian brain. In many cases, we have detailed information about the molecular characteristics of the channels and on how they can by modulated by G proteins and second messengers. However, we understand much less about how the many voltage-dependent channels expressed in a single central neuron work together to produce the firing patterns characteristic of that particular neuron. The goal of the proposed research is to understand how the firing properties of cerebellar Purkinje neurons are produced by particular combinations of ion channels. The work will combine current clamp recordings of action potential firing with a voltage-clamp analysis of the voltage-dependent sodium, potassium, and calcium channels underlying the action potentials. Studies on Purkinje neurons in cerebellar slices will examine ion channels and intrinsic membrane properties of dendrites and soma and will investigate how these interact under physiological conditions. The electrophysiological characterization will be complemented by immunocytochemical localization of particular sodium, calcium, and potassium channels. A preparation of dissociated cell bodies will allow a high-quality voltage-clamp of voltage-activated currents. Ionic substitution and specific channel blockers, especially peptide toxins, will be used to distinguish the contributions of particular channels. Action potential waveforms will be used as command voltages to determine the contribution of particular ion channels to particular firing patterns, with a special focus on understanding pacemaking activity and complex spikes. Understanding the mechanisms involved in regulating the electrical excitability of central neurons will help in understanding the normal function of the nervous system as well as pathophysiological states resulting from stroke, intoxication, and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS036855-08
Application #
6753534
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Stewart, Randall R
Project Start
1997-07-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
8
Fiscal Year
2004
Total Cost
$367,650
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Jo, Sooyeon; Bean, Bruce P (2017) Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States. Mol Pharmacol 91:277-286
Liu, Pin W; Blair, Nathaniel T; Bean, Bruce P (2017) Action Potential Broadening in Capsaicin-Sensitive DRG Neurons from Frequency-Dependent Reduction of Kv3 Current. J Neurosci 37:9705-9714
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
Liu, Pin; Jo, Sooyeon; Bean, Bruce P (2012) Modulation of neuronal sodium channels by the sea anemone peptide BDS-I. J Neurophysiol 107:3155-67
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
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
Jackson, Alexander C; Bean, Bruce P (2007) State-dependent enhancement of subthreshold A-type potassium current by 4-aminopyridine in tuberomammillary nucleus neurons. J Neurosci 27:10785-96
Puopolo, Michelino; Raviola, Elio; Bean, Bruce P (2007) Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J Neurosci 27:645-56
Bean, Bruce P (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451-65

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