| First Author | Chiu C | Year | 2008 |
| Journal | Ann Neurol | Volume | 64 |
| Issue | 3 | Pages | 284-93 |
| PubMed ID | 18825662 | Mgi Jnum | J:194736 |
| Mgi Id | MGI:5474678 | Doi | 10.1002/ana.21440 |
| Citation | Chiu C, et al. (2008) Developmental impact of a familial GABAA receptor epilepsy mutation. Ann Neurol 64(3):284-93 |
| abstractText | OBJECTIVE: A major goal of epilepsy research is to understand the molecular and functional basis of seizure genesis. A human GABA(A) gamma2 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. GABA(A) 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. |
