GABA Modulators in Epilepsy

GABA Modulators in Epilepsy

1. Why GABA is a seizure-control target

• A seizure is a transient alteration of behaviour caused by disordered, synchronous, rhythmic high-frequency firing of populations of cortical neurons; epilepsy is the disorder characterised by the risk of periodic, unpredictable seizures (G&G 14e Ch.20, p.385–386).
• The two principal amino-acid transmitters in the mammalian brain are GABA (γ-aminobutyric acid) — the major inhibitory transmitter — and glutamate — the major excitatory transmitter (G&G 14e Ch.20, p.387).
  • A seizure can be triggered by either a reduction of inhibitory (GABAergic) synaptic activity or an enhancement of excitatory (glutamatergic) synaptic activity; pharmacological studies confirm both limbs (G&G 14e Ch.20, p.387).
  • In isolated brain-slice models, a subtle reduction (≈20%) of inhibitory synaptic function is sufficient to produce epileptiform activity (G&G 14e Ch.20, p.388).
• Direct pharmacological proof of the GABA limb: antagonists of the GABA_A receptor (bicuculline, picrotoxin) or agonists of glutamate receptors provoke seizures in animals, whereas agents that enhance GABA-mediated inhibition suppress seizures across diverse models (G&G 14e Ch.20, p.387; KDT 8e Ch.29, p.429).
• Mechanistic principle: enhancing GABA-mediated synaptic inhibition increases Cl^- influx → membrane hyperpolarization → raises seizure threshold and reduces the propensity to fire high-frequency action potentials (G&G 14e Ch.20, p.388).
• One of the four major ASD mechanistic categories (G&G's classification) is "Enhancement of GABA neurotransmission through actions on GABA_A receptors, modulation of GABA metabolism, or inhibition of GABA reuptake" — this category defines the present topic (G&G 14e Ch.20, p.385).