The long term goal of this research program is to define the roles of various types of ion channels in the functioning of individual cortical neurons and complex cortical circuits. To achieve this goal, it is necessary to characterize the properties of the ion channels expressed in different cortical cell types, to determine the functional roles of these channels in controlling the firing properties of cortical neurons, and to delineate the mechanisms involved in the regulation and modulation of these channels by membrane voltage, neurotransmitters and intracellular second messengers. Our present focus is on intrinsic membrane properties, and the specific hypothesis being tested is that the presence of various types of ion channels underlies the expression of the """"""""regular-spiking"""""""", """"""""intrinsically bursting"""""""" and """"""""fast-spiking"""""""" electrophysiological phenotypes distinguished in in vivo and in vitro recordings from cortical neurons. To test this hypothesis directly, we have developed methods that enable us to identify callosal-projecting, superior colliculus-projecting and GABAergic, inhibitory (rat) visual cortical neurons in vitro and to characterize the intrinsic membrane properties of these cells in detail. Each of these cell populations was selected to correspond to one of the three phenotypes distinguished in in vitro cortical slice recordings. This research proposal is specifically focussed on examining the properties and the functional roles of the depolarization-activated and Ca++-activated K+ channels expressed in these three, distinct cortical cell types. Using the whole- cell variation of the patch clamp recording technique, initial experiments will characterize the time- and voltage-dependent properties and pharmacological sensitivities of the depolarization-activated K+ currents in isolated, identified callosal-projecting, superior colliculus-projecting and GABAergic inhibitory cortical neurons. Subsequent experiments on isolated cells and on identified cells in in vitro cortical slices will be aimed at determining the role of depolarization-activated K+ currents in shaping the waveforms of action potentials and in controlling the overall firing properties of these three cortical cell types. In the second phase of the project, a similar set and sequence of experiments will be completed to characterize the properties and the functional roles of the Ca++-activated K+ channels expressed in callosal-projecting, superior colliculus-projecting and GABAergic, inhibitory cortical neurons. It is unlikely that any direct clinical applications will result from the studies outlined in this proposal. It is expected, however, that the proposed experiments will clarify the types, distributions, and properties of the depolarization-activated and Ca++-activated K+ channels expressed in diverse neocortical cell types and provide insights into the functional roles of these K+ channels in controlling the firing properties of these cells. In addition, it is anticipated that insights gleaned from these studies will facilitate future functional analysis of the cortical circuits in which these different cell types participate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030676-08
Application #
6187846
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Chen, Daofen
Project Start
1992-12-01
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2002-05-31
Support Year
8
Fiscal Year
2000
Total Cost
$231,571
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Norris, Aaron J; Nerbonne, Jeanne M (2010) Molecular dissection of I(A) in cortical pyramidal neurons reveals three distinct components encoded by Kv4.2, Kv4.3, and Kv1.4 alpha-subunits. J Neurosci 30:5092-101
Norris, Aaron J; Foeger, Nicholas C; Nerbonne, Jeanne M (2010) Interdependent roles for accessory KChIP2, KChIP3, and KChIP4 subunits in the generation of Kv4-encoded IA channels in cortical pyramidal neurons. J Neurosci 30:13644-55
Norris, Aaron J; Foeger, Nicholas C; Nerbonne, Jeanne M (2010) Neuronal voltage-gated K+ (Kv) channels function in macromolecular complexes. Neurosci Lett 486:73-7
Laezza, Fernanda; Gerber, Benjamin R; Lou, Jun-Yang et al. (2007) The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J Neurosci 27:12033-44
Burkhalter, Andreas; Gonchar, Yuri; Mellor, Rebecca L et al. (2006) Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses. J Neurosci 26:12274-82
Yuan, Weilong; Burkhalter, Andreas; Nerbonne, Jeanne M (2005) Functional role of the fast transient outward K+ current IA in pyramidal neurons in (rat) primary visual cortex. J Neurosci 25:9185-94
Dong, Hongwei; Shao, Zhenwei; Nerbonne, Jeanne M et al. (2004) Differential depression of inhibitory synaptic responses in feedforward and feedback circuits between different areas of mouse visual cortex. J Comp Neurol 475:361-73
Dong, Hongwei; Wang, Quanxin; Valkova, Katia et al. (2004) Experience-dependent development of feedforward and feedback circuits between lower and higher areas of mouse visual cortex. Vision Res 44:3389-400
Pal, Sumon; Hartnett, Karen A; Nerbonne, Jeanne M et al. (2003) Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. J Neurosci 23:4798-802
Gonchar, Yuri; Turney, Stephen; Price, Joseph L et al. (2002) Axo-axonic synapses formed by somatostatin-expressing GABAergic neurons in rat and monkey visual cortex. J Comp Neurol 443:1-14

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