Since the early studies of epilepsy in man, considerable evidence exists indicating the presence of a striking gliosis at the epileptic foci. However, glia associated with an epileptic foci have not been well characterized. The major focus of this proposal is to study the in vitro and in vivo cellular properties of astrocytes derived from humans with temporal lobe epilepsy (TLE) who have undergone surgery for the management of epilepsy. The major effort in epilepsy research has been to understand the neuronal mechanisms underlying epileptogenesis. The emerging new understanding of the functions of glia in the CNS, which indicate that these cells may play a more intimate role in neuronal excitability, have strongly suggested the importance of reexaming the role of glia in epileptic foci using modern research techniques. Astrocytes are known to perform a number of homeostatic functions in the brain such as regulation of ions and neurotransmitters in the extracellular space. The hypothesis to be tested is that impairment of these known astrocyte functions, specifically examining the regulation of extracellular K+, glutamate, and GABA, may affect neuronal hyperexcitability at the seizure site. Ion channel and neurotransmitter expression will be studied in brain slices of human tissue from normally active cortex, hyperactive hippocampal-parahippocampal seizure foci, and glial neocortical tumors using whole cell patch-clamp recording techniques. Also, primary cultures of astrocytes will be used to examine the in vitro properties of astrocytes from these same areas, as well as measuring transport properties for ions and neurotransmitters. Also, astrocytes are known to swell in a number of pathological conditions, including epilepsy. This project will examine if such swelling can contribute to the hyperexcitability of the seizure focus. The understanding of the mechanisms of epileptogenesis in human seizure foci is essential to any rational development of new pharmacotherapeutic agents. The work proposed in this application will provide important basic information about the characteristics and functions of astrocytes at defined human seizure foci, information which could potentially be important for the development of new approaches to treating hitherto medically intractable forms of epilepsy.
| O'Connor, E R; Sontheimer, H; Spencer, D D et al. (1998) Astrocytes from human hippocampal epileptogenic foci exhibit action potential-like responses. Epilepsia 39:347-54 |
