In the mesial temporal lobe epilepsy syndrome (MTLE), 65% of surgical specimens show hippocampal sclerosis which consists of severe neuronal loss, and aberrant axon sprouting. We hypothesized that it is the reorganized inhibition on surviving neurons. Also, recent human studies indicate that sclerosis is associated with changes in: 1) NMDA and AMPA mRNA subunits; and 2) GABA and glutamate and transporters. Unfortunately, one problem with human studies is that the pathology is final and static, and it is difficult to discern the """"""""cause"""""""" of the epilepsy from the """"""""consequence"""""""" of repeated seizures without time course studies in animal models. This research project is designed to understand the pathophysiology of human hippocampal sclerosis by studying time course changes in animal models of spontaneous limbic epilepsy. We will: 1) Determine, using in situ hybridization techniques and immunocytochemistry, the time course and evolution of NMDA R1-2a-d and AMPA GluR1-3 receptor subunits, associated with spontaneous seizures in three chronic models of limbic epilepsy (intra-hippocampal kainate, systemic pilocarpine, and self-sustained limbic status epilepticus); and 2) in the same rat models, determine the time course and evolution of glutamate (EAAC1; GLT-1, and GLAST) and GABA transporters (GAT-1; and GAT4). The chronic animal models will be compared to kindled animals and our recent human studies, and the results correlated to hippocampal neuron loss and signals of aberrant axon sprouting. We hypothesize that compare to controls and kindled rats, animals with spontaneous limbic epilepsy will show increased hippocampal AMPA and NMDA subunits; 2) decreased astroglial glutamate and GABA transporters; and 3) increased in neuronal EAAC1 transporters. An increase in AMPA and NMDA receptors could lead to neuronal hyperexcitability, changes in GABA and glutamate transporters would raise or decrease intra- synaptic and extracellular GABA and glutamate levels, and these factors interacting with aberrant axon sprouting could generate mesial limbic seizures.
These Specific Aims will be accomplished by performing multiple histologic techniques on the same rats that have been intensively monitored for spontaneous seizures, and the resulting data will provide an important understanding of the molecular pathophysiology of hippocampal epilepsy, suggest pathogenic mechanisms of limbic seizures, and provide insights into possible ways of controlling the chronic seizures.
