Epilepsy is a major neurological disease in which large groups of neurons discharge synchronously resulting in behavioral seizures. In vitro studies of the electrophysiology of the hippocampus have greatly increased our understanding of the singleNeuron and circuit alterations that can lead to epileptic seizures. However, many relatively common forms of epilepsy involve Neuronal populations outside the hippocampus whose basic neurobiology is not well understood. In particular, glutamatergic Mossy cells in the dentate hilus are known to be critically involved in temporal lobe epilepsy but are only poorly understood at present. In addition, several recent animal studies have presented compelling evidence for two conflicting models of how mossy Cells may be causally involved in this form of epilepsy. The present proposal focuses on several critical aspects of the basic Neurobiology of normal rat mossy cells and will help to resolve this controversy regarding the function of mossy cells in temporal lobe epilepsy. We will utilize multiple neuropharmacological approaches to determine if mossy cells can initiate synchronous activity in vitro or can enhance synchronous discharges initiated by nearby CA3 hippocampal pyramidal cells. We will use selective blockers of iontropic glutamate receptors to antagonize normal ongoing spontaneous synaptic inputs to mossy Cells, then testing whether these cells can generate all-or-none burst discharges intrinsically. Related experiments will utilize selective group II metabotropic glutamate agonists to define the origin and possible function of these spontaneous synaptic inputs. Finally, we will use paired intracellular and simultaneous field and intracellular recordings to determine if mossy cells ire interconnected through recurrent excitatory synapses and if these or similar polysynaptic interactions can mediate Synchronized discharges in the dentate/hippocampal region. The results from these experiments will substantially increase our understanding of the neurobiology of these important hilar neurons and should resolve whether mossy cells, like neighboring CA3 pyramidal neurons, can initiate epileptic-like synchronized discharges. These results will also help reconcile the conflicting views of hilar function that resulted from recent studies of in vivo animal models of temporal lobe epilepsy and may reveal new therapeutic methods for treating this important disease.
