A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice

作者：Zhang Liang; Wither Robert G; Lang Min; Wu Chiping; Sidorova Darmos Elena; Netchev Hristo; Matolcsy Catherine B; Snead Orlando Carter; Eubanks James H^*

来源：Neuropsychopharmacology, 2016, 41(6): 1467-1476.

DOI：10.1038/npp.2015.323

Cortical network hyper-excitability is a common phenotype in mouse models lacking the transcriptional regulator methyl-CPG-binding protein 2 (MeCP2). Here, we implicate enhanced GABA(B) receptor activity stemming from diminished cortical expression of the GABA transporter GAT-I in the genesis of this network hyper-excitability. We found that administering the activity-dependent GABA(B) receptor allosteric modulator GS-39783 to female Mecp2(+/-)mice at doses producing no effect in wild-type mice strongly potentiated their basal rates of spontaneous cortical discharge activity. Consistently, administering the GABA(B) receptor antagonist CGP-35348 significantly decreased basal discharge activity in these mice. Expression analysis revealed that while GABA(B) or extra-synaptic GABA(A) receptor prevalence is preserved in the MeCP2-deficient cortex, the expression of GAT-I is significantly reduced from wild-type levels. This decrease in GAT-I expression is consequential, as low doses of the GAT-I inhibitor NO-711 that had no effects in wild-type mice strongly exacerbated cortical discharge activity in female Mecp2(+/-)mice. Taken together, these data indicate that the absence of MeCP2 leads to decreased cortical levels of the GAT-I GABA transporter, which facilitates cortical network hyper-excitability in MeCP2-deficient mice by increasing the activity of cortical GABA(B) receptors.

• 出版日期2016-5