Abstract
Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed transcriptional regulator with functional importance in the central nervous system. Loss-of-function mutations in MECP2 results in the neurodevelopmental disorder, Rett syndrome, whereas increased expression levels are associated with the neurological disorder, MECP2 duplication syndrome. Previous characterization of a mouse line overexpressing Mecp2 demonstrated that this model recapitulated key behavioral features of MECP2 duplication syndrome with specific deficits in synaptic plasticity and neurotransmission. Alterations in excitation/inhibition balance have been suggested to underlie neurodevelopmental disorders with recent data suggesting that picrotoxin (PTX), a GABAA receptor antagonist, rescues certain behavioral and synaptic phenotypes in a mouse model of Down syndrome. We therefore examined whether a similar treatment regimen would impact the behavioral and synaptic phenotypes in a mouse model of MECP2 duplication syndrome. We report that chronic treatment with low doses of PTX ameliorates specific behavioral phenotypes, including motor coordination, episodic memory impairments, and synaptic plasticity deficits. These findings suggest that GABAA receptor antagonists may offer a possible therapeutic target for the treatment of MECP2 duplication syndrome.
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Acknowledgements
This work was supported by National Institute of Health grant MH081060 (LMM) and a NARSAD Independent Investigator Award (ESN). We thank Dr Rudolf Jaenisch for generously providing the Tau-Mecp2 mice. We would also like to thank Elizabeth Gordon for assistance with breeding of the Tau-Mecp2 line. We would like to acknowledge Drs Ege Kavalali and Megumi Adachi for discussions and comments on the manuscript.
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Na, E., Morris, M., Nelson, E. et al. GABAA Receptor Antagonism Ameliorates Behavioral and Synaptic Impairments Associated with MeCP2 Overexpression. Neuropsychopharmacol 39, 1946–1954 (2014). https://doi.org/10.1038/npp.2014.43
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DOI: https://doi.org/10.1038/npp.2014.43
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