The regulation of inhibition in mammalian cortex is intimately involved with the development and control of epilectic events. An understanding of the factors which modulate inhibition could lead to the development of improved methods for treating epilepsy. This grant proposes to study the physiological and pharmacological processes which underlie normal synaptic inhibition in mammalian cortex, employing dissociated cell cultures of mammalian neocortex and hippocampus as model systems. The currents responsible for inhibition generated by GABA, the inhibitory neurotransmitter, will be analyzed using whole cell patch clamp and single electrode voltage clamp techniques. The Cl channel which GABA activates will be characterized, using gigaseal patch clamp techniques. The mechanism which underlies desensitization of the GABA response will be determined at the level of whole cell currents and single channels. Drugs which interact with the GABA receptor complex and other antiepileptic drugs will be examined for their effects on IPSPs, and their mechanisms of action at the level of channel kinetics will be determined. In addition, the mechanisms by which several cortical neuropeptides (SOM, CCK, VIP, ENK) act to modulate synaptic inhibition will be examined and their effects on channel kinetics will be determined. Other """"""""inhibitory"""""""" currents in the cortical neurons, especially Ca activated K and Cl currents, which may play important roles in the control of epileptogenic processes, will be examined. The channels underlying these currents will be characterized. The """"""""plasticity"""""""" of these events in relation to repetitive activation and the ability of drugs or neuropeptides to modulate these events will also be determined. It is hoped that an increased understanding of the physiological and pharmacological regulation of synaptic and non-synaptic inhibition in mammalian cortex will contribute toward the development of improved strategies for treating epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024927-02
Application #
3409942
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1986-09-01
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Sloviter, R S; Dichter, M A; Rachinsky, T L et al. (1996) Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol 373:593-618
Oh, D J; Dichter, M A (1994) Effect of a gamma-aminobutyric acid uptake inhibitor, NNC-711, on spontaneous postsynaptic currents in cultured rat hippocampal neurons: implications for antiepileptic drug development. Epilepsia 35:426-30
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Williams, K; Romano, C; Dichter, M A et al. (1991) Modulation of the NMDA receptor by polyamines. Life Sci 48:469-98
Wang, H L; Dichter, M; Reisine, T (1990) Lack of cross-desensitization of somatostatin-14 and somatostatin-28 receptors coupled to potassium channels in rat neocortical neurons. Mol Pharmacol 38:357-61
Dichter, M A; Wang, H L; Reisine, T (1990) Electrophysiological effects of somatostatin-14 and somatostatin-28 on mammalian central nervous system neurons. Metabolism 39:86-90

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