Deletion of the betaine–GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice

摘要: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in mammalian brain. Once released, it removed from extracellular space by cellular uptake catalyzed GABA transporter proteins. Four transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of GAT1 clinically available anti-epileptic drug tiagabine has an effective strategy for treatment some patients with partial seizures. Recently, investigational EF1502, which inhibits both BGT1, was found to exert anti-convulsant action synergistic that tiagabine, supposedly due inhibition BGT1. The present study addresses role BGT1 seizure control effect EF1502 developing exploring a new mouse line lacking exons 3-5 (slc6a12) gene. deletion this sequence abolishes expression mRNA. However, homozygous BGT1-deficient mice normal development show susceptibility indistinguishable wild-type variety threshold models including: corneal kindling, minimal clonic tonic extension tests, 6Hz test, i.v. pentylenetetrazol test. We confirm mRNA brain, but find levels are several hundred times lower than those mRNA; possibly explaining apparent lack phenotype. In conclusion, results do not support cannot provide mechanistic understanding synergism previously reported EF1502.