Developmental impact of a familial GABAA receptor epilepsy mutation

Objective: A major goal of epilepsy research is to understand the molecular and functional basis of seizure genesis. A human GABA(A) gamma 2 gene mutation (R43Q) is associated with generalized epilepsy. Introduction of this mutation into a mouse by gene targeting recapitulates the human phenotype demonstrating a strong genotype to phenotype link. GABAA receptors play a role in the moment-to-moment control of brain function and also on the long-term wiring of the brain by directing neuronal development. Our objective was to determine whether developmental expression of the mutation alters seizure susceptibility later in life. Methods: A tetracycline-based conditional model for activation of a hypomorphic Q43 disease allele was created and validated. Seizure susceptibility was assessed using the subcutaneous pentylenetetrazole model. Results: Seizure susceptibility was significantly reduced in mice where the Q43 allele was suppressed during development. Interpretation: These results demonstrate that a human epilepsy-causing mutation impacts network stability during a critical developmental period. These data suggest that identification of presymptomatic children may provide a window for therapeutic intervention before overt symptoms are observed, potentially altering the Course of epileptogenesis.