Temporal lobe epilepsy (TLE), a devastating seizure disorder that is difficult to control with anticonvulsant drugs, often develops following an initial insult to the CNS. In order to better understand the process of epileptogenesis and to develop innovative therapeutic approaches for the management of TLE, animal models have been developed that exhibit some of the hallmarks of this seizure disorder: a period of status epilepticus (SE) which serves as the initial insult to the CNS, a variable latent period during which seizures do not occur, and the eventual development of recurrent, spontaneous seizures of temporal lobe origin. Decades of research in such models have generated a vast amount of knowledge on the role of neurons in the hippocampus (HC) in TLE. However very little is currently known about the functional role in TLE of astrocytes: the other major cell type within the brain. Recently our laboratory utilized the kainic acid (KA) model of SE to investigate such `reactive' astrocytes. In this commonly used animal model of TLE, we made the novel discovery that astrocytes dramatically increase the expression of the ionotropic kainate receptor subunit, KA1. We hypothesize that activation of these newly expressed kainate receptors induces excitatory gliotransmission that depolarizes nearby CA1 pyramidal cells. Such excitatory gliotransmission in the hippocampus may have significant implications with respect to synchronization and seizure generation and this exploratory proposal will perform two specific aims to test this overall hypothesis.
Specific Aim 1 will use immunohistochemical and immunoblotting techniques to determine if KA- induced SE results in a long-term increase in expression of kainate receptors on astrocytes.
Specific Aim 2 will use the whole cell patch clamp technique to determine if activation of kainate receptors expressed on astrocytes induces gliotransmission that activates excitatory amino acid receptors in CA1 pyramidal cells in brain slices obtained from animals following KA-induced SE. It is anticipated that an increased understanding of the role of astrocytes in TLE will provide innovative molecular targets for the treatment of this frequently therapy-resistant seizure disorder.
Increasing evidence suggests that non-neuronal glial cells may contribute to seizure generation and epilepsy. Therefore, the proposed research will evaluate changes in a specific type of excitatory amino acid receptor that occur in glial cells in an animal model of epilepsy. It is anticipated that this work will reveal new potential therapeutic targets for the treatment of epilepsy. ? ? ? ?
| Wilcox, Karen S; Dixon-Salazar, Tracy; Sills, Graeme J et al. (2013) Issues related to development of new antiseizure treatments. Epilepsia 54 Suppl 4:24-34 |
| Vargas, Jay R; Takahashi, D Koji; Thomson, Kyle E et al. (2013) The expression of kainate receptor subunits in hippocampal astrocytes after experimentally induced status epilepticus. J Neuropathol Exp Neurol 72:919-32 |
| Gibbons, M B; Smeal, R M; Takahashi, D K et al. (2013) Contributions of astrocytes to epileptogenesis following status epilepticus: opportunities for preventive therapy? Neurochem Int 63:660-9 |
| Takahashi, D K; Vargas, J R; Wilcox, K S (2010) Increased coupling and altered glutamate transport currents in astrocytes following kainic-acid-induced status epilepticus. Neurobiol Dis 40:573-85 |
