Presynaptic gamma-aminobutyric acid (GABA) receptors play a central role in regulating excitatory and inhibitory synaptic transmission in the mammalian central nervous system. it has been proposed that the ability of these receptors to regulate glutamate release may be altered during development and in epilepsy. Recently a novel "desensitizing" GABAb receptor was discovered which participates in the regulation of excitatory transmission at functionally distinct glutamatergic synapses. This raises the possibility that changes in the type of receptor expressed during development or m epileptic brain may contribute to alterations in GABAb receptor function. The long term objective of the proposed research is to investigate the mechanism(s) underlying presynaptic GABAb receptor-mediated regulation of excitatory (glutamatergic) synaptic transmission during normal cerebral cortical development and in epileptic neocortex. The specific aims of the proposed research are: 1) to determine differences in the pharmacological and developmental profiles of the novel "desensitizing" and classical non- desensitizing presynaptic GABAb receptors which inhibit the cortical release of glutamate; 2) to compare the underlying receptor-effector coupling mechanism(s) used by these receptors, and determine if second messenger modulation of receptor function changes during development; and 3) to assess whether presynaptic GABAb receptor function is altered in human epileptic cortex, and if so, to determine the mechanism(s) underlying these changes. These aims will be achieved using standard whole-cell voltage-clamp (patch-clamp) and intracellular current-clamp recording techniques. Spontaneous and evoked glutamatergic synaptic events will be used to monitor the effects of exogenous activation of presynaptic GABAb receptors. These studies will be performed in embryonic rat cortical cell cultures, neonatal and adult rat brain slices, and human neocortical brain slices prepared from surgical waste tissue removed from patients with epilepsy during temporal lobe resection for relief from intractable seizures. The proposed research will provide important information immediately relevant to our understanding of the role of presynaptic GABAb receptors in the regulation of the release of glutamate during normal development and under pathophysiological (epileptic) conditions. More importantly, this work may have implications for the eventual design and use of novel therapeutic strategies based on targeting of drugs at specific subsets of functionally distinct glutamate releasing terminals. This approach may prove useful in the treatment of epilepsy and other pathophysiological conditions which involve overactivation of glutamate receptors.

R01NS033959

1995-04-01

2000-02-28