Date of Award
Doctor of Philosophy (PhD)
Professor R.J. Racine
Brief, localized electrical stimulation of the brain can elicit a short electrographic afterdischarge (AD). In the rat, repeated stimulation permanently increases the duration of the AD and can lead to the development of a generalized motor seizure. This process has been labelled "kindling" and has been utilized as a model of epilepsy and neural plasticity.
Hypotheses concerning the mechanism of the neural change produced by kindling typically specify either an excitatory enhancement or an inhibitory decrement. Of the inhibitory neurotransmitters that are likely to be involved, Υ-aminobutyric acid (GABA) is probably the least studied. The hypothesis that GABA hypofunction contributes to the establishment of the kindled response was tested by the experiments in this thesis. GABA is known to mediate recurrent inhibition in the dentate gyrus of the hippocampus, a structure ideally suited for electrophysiological investigation.
Double pulse stimulation of the perforant path input to the dentate gyrus was used in the following experiments to produce paired pulse depression in that site. This depression effect provided an estimate of GABA-mediated recurrent inhibition. The depression was, for example, enhanced by GABA agonist drugs and attenuated by drugs which block GABA transmission. Paired pulse depression was significantly increased following amygdala kindling and was further enhance to near maximal levels by subsequent kindling in the dentate. These results indicated that kindling increased, rather than reduced, inhibition in the dentate gyrus.
In addition, kindling did not increase the rate at which inhibition fails under conditions of excessive activation. Trains of 5 Hz stimulation, applied to the perforant path, caused paired pulse depression to disappear and elicited a brief AD. Following kindling, the latency to AD onset tended to be increased rather than shortened, suggesting an enhanced resistance to inhibitory failure.
Finally, receptor binding estimates of the number of GABA and associated benzodiazepine (Bz) receptors were made in several brain regions following kindling. While the number of GABA receptors, as measured by both ³H-GABA and ³H-Muscimol binding, was unaltered by kindling, Bz receptors were significantly increased in kindled amygdala and hippocampus. As the Bz receptor apparently functions to enhance GABA transmission, this finding suggests a possible mechanism for the enhanced inhibition observed in the evoked potential experiments.
Taken together, the results indicate that kindling does not produce a decrement in GABA-mediated inhibition in the hippocampus and, in fact, enhances it in an apparently compensatory manner. A possible mechanism for this long-term inhibitory potentiation is suggested to be the up-regulation of the Bz receptor.
Tuff, Lawrence Patrick, "The Effects of Kindling on GABA-mediated Inhibition in the Dentate Gyrus of the Rat" (1982). Open Access Dissertations and Theses. Paper 1554.