Temporal lobe epilepsy is the most common form of epilepsy in adults, and it is often medically intractable. In the dentate gyrus of patients with temporal lobe epilepsy granule cell axons reorganize. The new synaptic targets of granule cell axons must be identified. The possible targets in the dentate gyrus are other granule cells and GABAergic interneurons. Contacts with neighboring granule cells will form a recurrent excitatory circuit that could generate seizures. Contacts with GABAergic interneurons will strengthen the recurrent inhibitory circuit having an anti-epileptic effect. These alternatives are not mutually exclusive. This project will determine how the connectivity of granule cells changes in the epileptic brain.
The specific aims are to define the number of synaptic contacts formed and identify the postsynaptic cells before and after kainate induced granule cell axon reorganization. Individual granule cells will be labeled intracellularly in vivo with biocytin. Within the dentate gyrus their complete axon arbors will be 3-dimensionally reconstructed and measured. Using electron microscopy the synaptic density (number of synapses per axon length) of selected axon segments will be measured. Data on axon length and synapse density will be integrated to estimate the total number and distribution of synapses made by individual granule cells. Electron microscopy and post embedding immunocytochemistry for GABA will be used to determine the proportion of synapses formed with GABAergic versus non-GABAergic neurons. These experiments will provide new data on the connectivity of granule cells and establish an experimental approach for evaluating potential treatments designed to influence granule cell axon reorganization.
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