The long-term objective of our research program is to understand how mammalian motoneurons integrate synaptic inputs and transform them into changes in firing rate. The focus in this renewal application is on the effects of active dendritic conductances on these processes. Much of the precedent work on synaptic integration in motoneurons, including our own, has been carried out in anesthetized preparations in which the dendrites behave as passive core conductors. Under these conditions, individual synaptic currents are attenuated en route to the soma, and concurrently activated synaptic currents sum linearly or slightly less than linearly. However, in several types of unanesthetized animal preparations and in brain stem and spinal cord slices, motoneurons express a host of active dendritic conductances that dramatically alter the transmission of synaptic current to the soma and the integration of different synaptic input systems. The experiments proposed under Specific Aim 1 are designed to examine the integration of synaptic currents in motoneurons studied in unanesthetized, decerebrate cats. Tonic activity in descending monoaminergic fibers in the decerebrate preparation facilitates the expression of active dendritic conductances that mediate persistent inward currents, leading to a voltage- dependent amplification of synaptic input. The experiments proposed in Specific Aim 2 will examine the summation of synaptic currents in cat spinal motoneurons treated with internal potassium channel blockers, which have also been shown to induce voltage-dependent amplification of synaptic currents in motoneurons. The experiments in Specific Aim 3 will examine the dendritic mechanisms affecting the transfer of synaptic current to the soma, using glutamate iontophoresis onto dendritic branches of rat hypoglossal motoneurons studied in vitro. The motoneuron soma will be voltage-clamped, and the glutamate-evoked current will be measured at different clamp potentials before and after pharmacological blockade of different channel types. All of the experimental projects will be complemented by computer simulations using compartmental models of motoneurons with different types and distributions of dendritic conductances to help interpret the experimental data. Collectively, these experimental and simulation projects will provide new information on the integration of multiple synaptic inputs by motoneurons, and how motoneurons transform synaptic inputs into frequency- modulated spike trains outputs.
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