抄録
Strengthening GABA-A receptor α1 subunit-mediated inhibition with diazepam triggers ocular dominance (OD) plasticity prematurely (Fagiolini et al., 2004). Yet, the endogenous determinant of critical period (CP) induction remains unknown. Several biochemical analyses intriguingly reveal an elevated GABA uptake with a peak before the CP onset. The main GABA transporter (GAT1) localized to inhibitory axon terminals may be responsible for this transient activity based on its developmental expression profile. Here, we tested directly whether loss of GAT1 function regulates CP onset. In GAT1 knockout (KO) mice, neuronal response strength in visual cortex was normal, but prolonged discharge reflecting weak intracortical inhibition was lost earlier, suggesting an accelerated maturation of GABA function in vivo. Brief monocular deprivation (MD) revealed that OD plasticity of GAT1 KO mice was prematurely activated and rapidly eliminated. When CP onset is delayed by genetic disruption of GABA synthesis, infusion of a GAT1 inhibitor into visual cortex concomitant with MD restored robust OD shifts. Similarly, natural CP delay by dark-rearing is counteracted by diazepam treatment (Iwai et al., 2003) and was also prevented by loss of GAT1. Interestingly, western blot analysis showed that 2d diazepam treatment in the dark triggers a reduction of GAT1 expression, similar to the normal developmental decline in the light. Indeed, GAT1 heterozygous mice mimic such a downregulation and also exhibited an accelerated CP. These findings indicate that GAT1 expression acts as a "brake" to delay CP onset. [J Physiol Sci. 2006;56 Suppl:S34]
