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.
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