Kainate Receptors in Synaptic Transmission

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DESCRIPTION (provided by applicant): Kainate receptors (KARs) regulate neuronal excitability, and their global activation induces seizures and neuronal toxicity similar to that seen in epilepsy. Examination of KARs in synaptic function has largely focused on presynaptic KARs that appear to modulate neurotransmitter release. However, there is also clear evidence that KARs are located on the postsynaptic dendritic membranes of many neurons, and their role in synaptic physiology is unclear. KAR currents decay more slowly than AMPA currents, a property that may allow KARs to modulate the spread and integration of dendritic signals. Recent modeling of KAR function in response to afferent firing suggested that KAR activation could produce a tonic depolarization and increase neuronal excitability even at relatively low firing frequencies. This feature of KARs may confer a unique role in synaptic integration as well as in the timing and frequency of action potentials. While this is an intriguing hypothesis, it has not been directly tested. Our underlying hypothesis, based in part upon our preliminary data, is that postsynaptic KARs modulate firing frequency and integration of dendritic signaling in a cell-dependent manner. A direct test of this hypothesis will require examination of postsynaptic KARs in isolation from presynaptic KARs, with subcellular temporal and spatial resolution similar to that of synaptic activation. We will test the hypothesis that postsynaptic KARs are targeted to different dendritic regions of inhibitory and excitatory neurons in a cell-specific manner, and that postsynaptic dendritic KARs activation increases spike frequency in spontaneously firing inhibitory. Finally, we will test the hypothesis that postsynaptic dendritic KARs increase dendritic excitability and backpropagation of action potentials in hippocampal slice neurons. These experiments will be carried out using local photolysis, electrophysiology, and confocal imaging. These experiments will provide valuable new information about the role of postsynaptic, dendritic KARs in synaptic signaling and cell excitability.