title: NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2.
abstract: 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.
authors.affiliation: FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Severine
authors.initials: S
authors.lastname: Durand
authors.forename: Annarita
authors.initials: A
authors.lastname: Patrizi
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Quast
authors.forename: Lea
authors.initials: L
authors.lastname: Hachigian
authors.forename: Roman
authors.initials: R
authors.lastname: Pavlyuk
authors.forename: Alka
authors.initials: A
authors.lastname: Saxena
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Takao K
authors.initials: TK
authors.lastname: Hensch
authors.forename: Michela
authors.initials: M
authors.lastname: Fagiolini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D015518:Rett Syndrome / Q000473:pathology / Q000503:physiopathology*; D014787:Vision Tests; D014792:Visual Acuity / Q000502:physiology*; D014793:Visual Cortex / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D014795:Visual Pathways / Q000473:pathology / Q000502:physiology / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C120997:NR2A NMDA receptor; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate