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

Autor: Zhang L; Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; University of Toronto Epilepsy Research Program, University of Toronto, Toronto, ON, Canada.; Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada., Wither RG; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada., Lang M; University of Toronto Epilepsy Research Program, University of Toronto, Toronto, ON, Canada.; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada., Wu C; Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada., Sidorova-Darmos E; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada., Netchev H; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada., Matolcsy CB; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada., Snead OC; University of Toronto Epilepsy Research Program, University of Toronto, Toronto, ON, Canada.; Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada., Eubanks JH; University of Toronto Epilepsy Research Program, University of Toronto, Toronto, ON, Canada.; Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada.; Department of Surgery (Neurosurgery), University of Toronto, Toronto, ON, Canada.
Jazyk: angličtina
Zdroj: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2016 May; Vol. 41 (6), pp. 1467-76. Date of Electronic Publication: 2015 Oct 26.
DOI: 10.1038/npp.2015.323
Abstrakt: 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 GABAB receptor activity stemming from diminished cortical expression of the GABA transporter GAT-1 in the genesis of this network hyper-excitability. We found that administering the activity-dependent GABAB 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 GABAB receptor antagonist CGP-35348 significantly decreased basal discharge activity in these mice. Expression analysis revealed that while GABAB or extra-synaptic GABAA receptor prevalence is preserved in the MeCP2-deficient cortex, the expression of GAT-1 is significantly reduced from wild-type levels. This decrease in GAT-1 expression is consequential, as low doses of the GAT-1 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-1 GABA transporter, which facilitates cortical network hyper-excitability in MeCP2-deficient mice by increasing the activity of cortical GABAB receptors.
Databáze: MEDLINE
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