Creating a molecular map of the neuronal surface

The most fundamental function of nerve cells is the integration of their synaptic inputs to generate action potentials (APs). It is a generally accepted view that APs are generated in the axon initial segment. However, input synapses are usually distributed over a large dendritic tree. Because of this spatial arrangement, the distance between a synapse and the site of output generation varies to a tremendous extent, resulting in differential filtering of postsynaptic responses by the dendrites. Thus, if dendrites were passive, the effect of a synapse on output generation would depend on its dendritic location. However, in the past decades, it has become apparent that dendrites of most nerve cells are not passive, but contain a large number of voltagedependent ion channels, which endow dendritic trees with an unanticipated computational power. The molecular identity, exact location and density of voltage-gated ion channels in small subcellular compartments on the axo-somato-dendritic surface determine their roles in synaptic integration and output generation. Our work using high resolution immunolocalization approaches demonstrated that many ion channel subunits show different distribution patterns on the surface of distinct neuron types (cell typespecific distributions). In addition, the ion channel content of distinct subcellular compartments is highly unique (subcellular compartmentspecific distributions). By studying the subcellular distribution of HCN1, Kv1.1, Kv1.2, Kv2.1, Kv4.2, Kir3.2, Nav1.6 voltage-gated ion channel subunits we have reached the conclusion that all examined ion channel subunits have different axo-somato-dendritic distributions on the surface of hippocampal CA1 pyramidal cells. Now, the aim of our Laboratory is to extend these investigations with special interest to voltage-gated Ca2+ channels and voltage-independent ion channels that are responsible for determining the passive electrical properties of the neurons. Hands-in-hands with these experiments, in silico multicompartmental modeling is used to create functionally testable predictions of the functional consequences of different ion channel distributions. In vitro patch-clamp electrophysiology and two-photon imaging are also carried out to test the model predictions.