The role of gamma-aminobutyric acid in the mechanism of seizures

Abstract

The knowledge that GABA is an inhibitory neurotransmitter substance in brain has spurred a prodigious research effort to implicate GABA in the etiology of seizures. Such an involvement for GABA can occur theoretically at either of two levels, at the level of its metabolism or at the level of its functioning. Convulsant agents such as picrotoxin and bicuculline appear to act by impairing the functioning of GABA at the postsynaptic receptor site, but virtually nothing is known about the attendant molecular events although a major expansion of knowledge in this area may be expected within the next decade. In contrast, a vast amount of data has accumulated with respect to changes in GABA metabolism induced by convulsant agents such as the hydrazines, hydrazides, and hyperbaric oxygen. The problem in this case lies in the interpretation of the data. Are the changes in GABA metabolism the cause of the seizures? There is clearly no simple relationship between seizure activity and any single parameter of GABA metabolism, be it the GABA content of the brain, or the rate of uptake of GABA by cellular components, or the activity of the GABA-synthesizing and degrading enzyme systems, GAD and GABA-T respectively. This finding may, however, be illusory since the parameters of GABA metabolism were in most cases measured using preparations from intact brain tissue. Observed changes in the parameters may not accurately reflect events at a critical subcellular location such as the synaptic cleft. Thus there may well be a simple relationship between the concentration of GABA in the synaptic cleft and seizure activity. Unfortunately the limitations of current technology preclude the testing of this possibility. The author has, however, developed an equation on an empirical basis which provides an excellent relationship between the excitable state of the brain and a function of GABA metabolism which incorporates both changes in GABA level and changes in GAD activity. This equation has been used successfully to explain and rationalize previously anomalous results with respect to changes in GABA metabolism associated with the action of both convulsant and anticonvulsant agents. The concept embodied in the equation is that the excitable state of brain is determined primarily by the rate of synthesis of GABA but that reflects changes in the concentration of GABA in the synaptic cleft has been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)