The distribution and modulation of potassium channels in the dentrites of layer V pyramidal cells of the entorhinal cortex (360G-Wellcome-063247_Z_00_Z)

Layer V pyramidal cells of the EC are essential for the transfer of information from the hippocampus to the neocortex. These cells differ from other pyramidal cells in the central nervous system in demonstrating intense electrical activity. The pattern of action potential firing is greatly influenced by the density and properties of the K+ channels present in neurones. As yet, however, relatively little is known about K+ channels in these neurones. To understand fully the electrical activity of neurones, it is essential to know about the properties of ion channels present in both dendrites and soma. Most synaptic inputs are located on dendrites and the firing pattern of a neurone is the consequence of the co-ordination and transformation of incoming synaptic input within dendrites as well as the soma. Dendrites possess a variety of channels and receptors, which can differ from those located on the soma in their densities as well as their pharmacological and biophysical properties. In hippocampal CA1 pyramidal neurones (e.g.), the A-type K+ channel density increases linearly with distance from the soma. This is an important discovery as it explains the reason why action potentials are not normally initiated in dendrites, even though the dendrites of these neurones possess high densities of both Na+ and Ca2+ channels. It also explains why action potential amplitudes in dendrites are smaller than at the soma. Lack of the large conductance Ca2+-activated K+ channels (BK channels) in dendrites cause action potentials to be broader than at the soma. These changes in channel density, however, do not occur in all neurones (e.g. in neocortical pyramidal cells, it has been suggested that there is no increase in density of the A-type K+ channels). Because of the differential distribution of voltage-gated ion channels, the integrative action and firing pattern of neurones will vary. The principle aim of this study, therefore, is to investigate the somato-dendritic distributions of voltage-gated (the A-type and delayed rectifier type) K+ channels and BK channels in the EC layer V pyramidal neurones using both electrophysiological and immuno-histochemical approaches. The biophysical and pharmacological properties of these channels on the apical dendrite and the soma will also be examined. The distribution of channels in dendrites is of additional importance as it has recently been shown that action potentials initiated in the soma can backpropagate into dendrites. The integration of synaptic input in dendrites will be influenced by this back propagation. Accordingly, the role of the voltage-gated K+ channels in action potential backpropagation in EC layer V pyramidal neurones will also be studied. The A-type K+ channel channels in CA1 pyramidal neurones are subject to inhibition by protein kinase A (PKA), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). This provides another way in which action potential amplitude and backpropagation can be modulated. Hence, the effects of PKA, PKC and MAPK on the biophysical properties of the A-type and delayed rectifier type K+ channels in dendrites will be studied. The experiments proposed will provide information that will be essential in understanding the mechanisms regulating excitability in the layer V EC neurones. The information obtained will also be of use in understanding the role of the EC in diseases such as epilepsy.