Mossy cells in the hilar region are important but relatively understudied contributors to integration of cortical input to the hippocampus. Signaling mechanisms that impact mossy cell excitability and synaptic function are relevant to physiological network function, such as encoding of patterns of input, and play a role in pathological adaptations, as occur in epilepsy. Kainate receptors play important modulatory roles in network excitability elsewhere in the hippocampus through diverse functional activities that are neuron- and synapse-specific. How kainate receptors might contribute to excitatory signaling in hilar mossy cells and between mossy cells and either hilar interneurons or dentate granule cells is entirely unknown and is the focus of 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 to seizures in rodent seizure models.
In Specific Aim 1, we will determine the role and composition of kainate receptors in mossy cells, focusing particularly on postsynaptic kainate receptor function at granule cell - mossy cell synapses. The subunit composition of mossy cell kainate receptors will be determined using a combination of pharmacological tools and gene-targeted mice.
In Specific Aim 2, we will examine potential contributions by kainate receptors to signaling between mossy cells and dentate granule cells or hilar interneurons. The architecture of mossy cell projections has made studying these synapses challenging. We will develop a new mouse model in which channelrhodopsin is selectively expressed in mossy cells and subsequently photostimulate inputs to granule cells or hilar interneurons independent of either perforant path or CA3 collaterals. Pre- and postsynaptic function, mechanisms of short- and long-term synaptic plasticity, and the role of kainate receptors at these synapses will be determined for the first time. These studies will elucidate the physiological role played by kainate receptors in hilar circuits and lay the framework for understanding their pathological role in network hyperexcitability in seizure states.

Public Health Relevance

Communication between neurons in the hippocampus underlie memory processing and can go awry to generate seizures. In this project we will examine how signaling proteins influence excitability in a connected network of neurons using physiological approaches. Our studies will establish a framework for exploring how hyperexcitability observed in animal models of epilepsy are transduced in part by aberrant signaling between the hilus and the dentate gyrus, two parts of the hippocampus that are important for processing of input from the cortex.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Whittemore, Vicky R
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Northwestern University at Chicago
Schools of Medicine
United States
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Hedrick, Tristan P; Nobis, William P; Foote, Kendall M et al. (2017) Excitatory Synaptic Input to Hilar Mossy Cells under Basal and Hyperexcitable Conditions. eNeuro 4: