NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2

Neuron. 2012 Dec 20;76(6):1078-90. doi: 10.1016/j.neuron.2012.12.004.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / physiology*
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neurons / metabolism
  • Parvalbumins / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Rett Syndrome / pathology
  • Rett Syndrome / physiopathology*
  • Vision Tests
  • Visual Acuity / physiology*
  • Visual Cortex / pathology
  • Visual Cortex / physiology*
  • Visual Cortex / physiopathology
  • Visual Pathways / pathology
  • Visual Pathways / physiology
  • Visual Pathways / physiopathology

Substances

  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • NR2A NMDA receptor
  • Parvalbumins
  • Receptors, N-Methyl-D-Aspartate