Epilepsy and the GABA-hypothesis a brief review and some examples

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Epilepsy is associated with alterations in GABAergic neurotransmission.
• The GABA-hypothesis suggests reduced GABAergic inhibition causes epilepsy.
• Convulsants and anticonvulsants can modulate GABAergic system components.

Purpose of the Study:

• To investigate the effects of exogenous and endogenous convulsants on GABAergic inhibition.
• To examine the interaction of these convulsants with the postsynaptic GABAA receptor.
• To evaluate the relevance of these findings to the GABA-hypothesis of epilepsy.

Main Methods:

• Review of existing literature on GABAergic alterations in epilepsy models and human epilepsy.
• Experimental testing of pentylenetetrazol (PTZ), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), and guanidino compounds on GABA responses in mouse neurons.
• Assessment of the effects of benzodiazepine receptor antagonist CGS 9896.

Main Results:

• PTZ and DMCM reduced GABA responses in a dose-dependent manner.
• CGS 9896 antagonized DMCM-induced inhibition but not PTZ-induced inhibition.
• Guanidino compounds (elevated in uremia/hyperargininemia) decreased both GABA and glycine responses, independent of CGS 9896.
• Convulsants interact with distinct sites on the postsynaptic GABAA receptor.

Conclusions:

• The studied convulsants inhibit GABAergic inhibition via distinct postsynaptic GABAA receptor sites.
• These findings support the GABA-hypothesis of epilepsy.
• The mechanisms may contribute to epileptogenicity in animal models and have implications for uremia and hyperargininemia.