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.
| Vakharia, Vejay N; Duncan, John S; Witt, Juri-Alexander et al. (2018) Getting the best outcomes from epilepsy surgery. Ann Neurol 83:676-690 |
| Engel Jr, Jerome; Bragin, Anatol; Staba, Richard (2018) Nonictal EEG biomarkers for diagnosis and treatment. Epilepsia Open 3:120-126 |
| Engel Jr, Jerome (2018) The current place of epilepsy surgery. Curr Opin Neurol 31:192-197 |
| Kerr, Wesley T; Janio, Emily A; Braesch, Chelsea T et al. (2018) An objective score to identify psychogenic seizures based on age of onset and history. Epilepsy Behav 80:75-83 |
| Engel Jr, Jerome (2018) Epileptogenesis, traumatic brain injury, and biomarkers. Neurobiol Dis : |
| Frauscher, Birgit; Bartolomei, Fabrice; Kobayashi, Katsuhiro et al. (2017) High-frequency oscillations: The state of clinical research. Epilepsia 58:1316-1329 |
| Jozwiak, Sergiusz; Becker, Albert; Cepeda, Carlos et al. (2017) WONOEP appraisal: Development of epilepsy biomarkers-What we can learn from our patients? Epilepsia 58:951-961 |
| Weiss, Shennan Aibel; Alvarado-Rojas, Catalina; Bragin, Anatol et al. (2016) Ictal onset patterns of local field potentials, high frequency oscillations, and unit activity in human mesial temporal lobe epilepsy. Epilepsia 57:111-21 |
| Jette, Nathalie; Engel Jr, Jerome (2016) Refractory epilepsy is a life-threatening disease: Lest we forget. Neurology 86:1932-3 |
| Engel Jr, Jerome (2016) When is temporal lobe epilepsy not temporal lobe epilepsy? Brain 139:309-12 |
Showing the most recent 10 out of 89 publications
