Epilepsy arising from the temporal lobes is particularly devastating because it is both common and commonly resistant to symptomatic therapy with anticonvulsants. Preclinical and clinical studies support the idea that an episode of status epilepticus followed by recovery contributes to development of temporal lobe epilepsy months or years later. Insight into the mechanisms by which status epilepticus induces temporal lobe epilepsy may facilitate developing preventive and/or disease modifying therapies. We recently discovered a molecular signaling pathway by which status epilepticus induces temporal lobe epilepsy, namely activation of the brain- derived neurotrophic factor receptor, TrkB. A major unresolved question, to be addressed in this application, is how this signaling is transformed into the cellular and circuit modifications that underlie temporal lobe epilepsy. The anatomic locale at which status epilepticus induced activation of TrkB provides a valuable clue to the cellular consequences. The principal site was the synaptic boutons of the mossy fiber axons of hippocampal dentate granule cells. The objective of this application is to test three facets of our unifying hypothesis: a) that status epilepticus induces plasticities of mossy fiber synapses with both CA3 pyramidal cells and inhibitory interneurons; b) that status epilepticus induction of these plasticities requires TrkB; and c) that transmitter release from the mossy fibers underlies expression of temporal lobe epilepsy.
Temporal lobe epilepsy is a common and commonly devastating form of human epilepsy for which there is only symptomatic therapy. Understanding the mechanisms of temporal lobe epilepsy will facilitate development of preventive and/or disease modifying therapies. The proposed studies seek to elucidate the cellular and circuit mechanisms of a mouse model of temporal lobe epilepsy.