THE ROLE OF MICROTUBULE ASSOCIATED TAU PROTEIN IN THE EPILEPTOGENESIS AND ASSOCIATED INHIBITORY NEUROPLASTICITY OF TLE

Abstract

Studies of the microtubule-associated protein, tau suggest its promise as a potential target for epilepsy disease modification, but mechanisms underlying tau’s effects on seizures are not well-defined. Acquired temporal lobe epilepsy (TLE) is the most prevalent form of focal epilepsy, yet the impact of tau expression on the process of TLE development is unexplored. These studies investigated tau’s role in the epileptogenesis of acquired TLE using the intrahippocampal kainate (IHK) model in mice lacking tau expression (i.e., tau-/- mice).Background information on microtubule associated tau protein and its role in cellular and synaptic physiology, organization and circuitry of the dentate gyrus of the hippocampus, TLE, rodent models of TLE, and literature review of tau protein and seizures is provided in Chapter 1. The study in Chapter 3 examined epileptiform activity during status epilepticus (SE) after IHK injection and assessed the subsequent development of spontaneous recurrent seizures (SRS) using video and video-electroencephalography (v-EEG). Results demonstrate that the lack of tau expression did not prevent evoked seizures or the development of TLE but reduced the number of convulsive seizures during SE and the severity of spontaneous seizures after TLE developed which has not been demonstrated in the context of an acquired TLE model. To investigate synaptic changes associated with TLE development in the dorsal dentate gyrus, whole-cell patch clamp electrophysiology was used to assay excitatory and inhibitory synaptic input to dentate granule cells (DGCs). Results show that DGCs in tau-/- mice normally receive less inhibitory input compared to than in wildtype controls, and after tau-/- mice develop TLE, DGCs recieve increased contralateral inhibitory input. This suggests that deletion of tau protein modifies seizure expression, potentially via mechanisms involving inhibitory synaptic circuits in the dentate gyrus but does not prevent epileptogenesis. To further examine how development of TLE modifies inhibitory synaptic reorganization at sites distal to the kainate lesion, in Chapter 4, assays of excitability and synaptic transmission in DGCs in the ventral hippocampus were performed using whole-cell patch clamp electrophysiology. Results demonstrate development of TLE in mice lacking tau expression is associated with widespread inhibitory synaptic reorganization in the dentate gyrus that may contribute to altered seizure expression and epileptogenesis, expanding on the results in Chapter 3. In Chapter 5, I explored the hypothesis that development of TLE in mice lacking tau expression is associated with modified inhibitory synaptic connections and plasticity between inhibitory interneurons and vDGCs. Using whole-cell patch clamp electrophysiology with direct optogenetic stimulation of interneurons in the ventral dentate gyrus. Results demonstrated that TLE development in mice lacking tau expression results in net strengthening of inhibition that is associated with increased synaptic contacts between interneurons and vDGCs. This indicated a regulatory role of tau expression in inhibitory interneuron synaptogenesis that may be responsible for modified epileptogenesis and seizure expression in the IHK model. Taken together, Chapters 3, 4, and 5 suggest a regulatory role of microtubule associated tau protein in inhibitory synaptic transmission in the local dentate gyrus circuit which may underlie its distinct influence on seizures and epileptogenesis.