A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice.
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.
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.
Liang
L
Zhang
Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.|Department of Physiology, University of Toronto, Toronto, ON, Canada.
Robert G
RG
Wither
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.
Min
M
Lang
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.
Chiping
C
Wu
Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.|Department of Physiology, University of Toronto, Toronto, ON, Canada.
Elena
E
Sidorova-Darmos
Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.
Hristo
H
Netchev
Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.
Catherine B
CB
Matolcsy
University of Toronto Epilepsy Research Program, University of Toronto, Toronto, ON, Canada.|Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada.
Orlando Carter
OC
Snead
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.
James H
JH
Eubanks
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology; D004567:Electrodes, Implanted; D004569:Electroencephalography; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D058805:GABA Uptake Inhibitors / Q000494:pharmacology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
D003517:Cyclopentanes; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D009943:Organophosphorus Compounds; D011743:Pyrimidines; C493414:Slc6a1 protein, mouse; C066430:CGP 35348