MOLECULAR MICROANATOMY--STRUCTURE /FUNCTION RELATIONSHIP

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

The objective of this research proposal is to investigate the alterations in fascia dentata GABAergic interneuron excitation in human temporal lobe epilepsy (TLE) and the intrahippocampal kainate rat TLE model. Previous studies supports the concert that hippocampal granule cells show increased excitation in TLE. This could be a mechanism that initiates limbic seizures and/or promotes seizure spread. TLE patients do not have continuous seizures, however, suggesting that inhibitory mechanisms must exist to control hyperexcitable granule cells. In addition, changes in GABAergic inhibition in TLE may alter properties of the fascia dentata "gate", and contribute to hippocampal epileptogenesis. We hypothesize that one possible seizure-suppressing mechanism may be altered fascia dentata interneuron excitation as a consequence of aberrant axon sprouting. Specific hypotheses to be tested include: i) In chronic epileptogenic hippocampi with axon sprouting and fast ripples, we propose that interneurons will show altered AMPA, NMDA, and kainate receptor-mediated excitation. This hypothesis tests components of the "GABA" hypothesis,. ii) In intrahippocampal kainate rats, changes in fascia dentata interneuron excitation begins during the latent period before spontaneous seizures but after the appearance of axon sprouting and fast ripples. iii) Interneuron excitation may be different for parasomal (basket and axo-axonic cells) compared with dendritic inhibitory interneurons. This hypothesis tests aspects of the "dormant basket cell" hypothesis. These hypotheses will be tested by performing anatomic to discern changes in glutamate receptor subunit mRNA levels over identified fascia dentata GABAergic interneurons, and parallel hippocampal slice electrophysiological studies where interneuron glutamate receptor functions are blocked using selective investigation of mechanisms that alter neuronal excitation and inhibition in TLE, and are important for elucidating fundamental concepts that explain TLE epileptogenesis. The significance of our project is that it provides information to understand pathophysiological mechanisms that may contribute or "cause" TLE that will lead to new approaches in the diagnosis, prevention and/or treatment of this disease. This is an important public health issue in that TLE is the most common intractable seizure syndrome mainly treated with resective surgery.