Mossy cells in the hilar region are important but relatively understudied contributors to integration of cortical input to the hippocampus. These glutamatergic neurons resemble CA3 pyramidal neurons in that they have large, bulbous proximal dendrites that form the sites of contact for bouton-like synapses arising from mossy fiber axons that originate in dentate granule cells. Unlike CA3 pyramidal neurons, however, the inner molecular layer of the dentate gyrus represents a primary target of mossy cell efferent axons, where they innervate granule cells on proximal dendrites. In this project we will determine if kainate receptors contribute to either efferent or afferent signaling in mossy cells. This objective is relevant to models of temporal lobe epilepsy because (i) mossy cells are central to the two predominant models of circuit hyperexcitability in chronic forms of temporal lobe epilepsy, and (ii) aberrant kainate receptor function was recently shown to contribute seizures in similar models. In Specific Aim 1, we will use a new mouse model expressing channelrhodopsin selectively in mossy cells to functionally isolate and analyze the robust projections from mossy cells to contralateral granule cells. These synaptic properties have not been studied in isolation to date because of the technical difficulty inherent in stimulation to the exclusion of other afferent pathways to dentate granule cells; optogenic approaches and the new mouse model afford an entry point for characterization of this excitatory synapse. In Specific Aim 2, we will determine the role and composition of postsynaptic kainate receptors at granule cell – mossy cell synapses. These studies will lay the framework for understanding both the physiological role played by kainate receptors in these first two excitatory synapses in the hippocampal formation and their pathological role in initiating or propagating hyperexcitability in seizure states.
|Effective start/end date||9/1/14 → 8/31/17|
- National Institute of Neurological Disorders and Stroke (5R21NS090040-02)