NMDA Receptor Regulation Prevents Regression of Visual Cortical Function in the Absence of Mecp2

Brain function is shaped by postnatal experience and vulnerable to disruption of Methyl-CpG-binding protein, Mecp2, in multiple neurodevelopmental disorders. How Mecp2 contributes to the experience-dependent refinement of specific cortical circuits and their impairment remains unknown. We analyzed v...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2012-12, Vol.76 (6), p.1078-1090
Main Authors: Durand, Severine, Patrizi, Annarita, Quast, Kathleen B., Hachigian, Lea, Pavlyuk, Roman, Saxena, Alka, Carninci, Piero, Hensch, Takao K., Fagiolini, Michela
Format: Article
Language:English
Subjects:
Animals
Autism
Behavior
Biomarkers
Brain
Defects
Disease Models, Animal
Female
Gene expression
Male
Methyl-CpG-Binding Protein 2 - genetics
Methyl-CpG-Binding Protein 2 - physiology
Mice
Mice, Knockout
Nerve Degeneration - pathology
Nerve Degeneration - physiopathology
Neurons
Neurons - metabolism
Parvalbumins - metabolism
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - physiology
Rett Syndrome - pathology
Rett Syndrome - physiopathology
Rodents
Variance analysis
Vision Tests
Visual Acuity - physiology
Visual Cortex - pathology
Visual Cortex - physiology
Visual Cortex - physiopathology
Visual Pathways - pathology
Visual Pathways - physiology
Visual Pathways - physiopathology
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Summary:Brain function is shaped by postnatal experience and vulnerable to disruption of Methyl-CpG-binding protein, Mecp2, in multiple neurodevelopmental disorders. How Mecp2 contributes to the experience-dependent refinement of specific cortical circuits and their impairment remains unknown. We analyzed vision in gene-targeted mice and observed an initial normal development in the absence of Mecp2. Visual acuity then rapidly regressed after postnatal day P35–40 and cortical circuits largely fell silent by P55-60. Enhanced inhibitory gating and an excess of parvalbumin-positive, perisomatic input preceded the loss of vision. Both cortical function and inhibitory hyperconnectivity were strikingly rescued independent of Mecp2 by early sensory deprivation or genetic deletion of the excitatory NMDA receptor subunit, NR2A. Thus, vision is a sensitive biomarker of progressive cortical dysfunction and may guide novel, circuit-based therapies for Mecp2 deficiency. ► Visual acuity is a reliable biomarker of cortical regression in the absence of Mecp2 ► Hyperconnected PV circuits anticipate loss of spontaneous activity and vision ► Developmental NR2A regulation rescues PV circuits, cortical activity, and vision ► These data suggest circuit-based therapies independent of Mecp2 for RTT syndrome Durand et al. demonstrate that hyperconnectivity of a selective inhibitory circuit precedes regression of visual function in mouse models of Rett Syndrome. Cortical dysfunction is rescued by environmental and genetic manipulation and may guide circuit-based therapies for Mecp2 deficiency.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2012.12.004