title: Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits.
abstract: BACKGROUND
  Early postnatal experience shapes N-methyl-D-aspartate receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons.
  
  
  METHODS
  We combined whole-cell patch clamp recordings (n = 440) of NMDAR-mediated currents from layer-4-to-layer-2/3 synapses onto pyramidal and green fluorescent protein labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30, and 45 postnatal days) with array tomography three-dimensional reconstructions of NMDAR subunits GluN2A- and GluN2B-positive synapses onto PV cells.
  
  
  RESULTS
  We show that the trajectory of the NMDAR subunit switch is slower in PV interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MECP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2-knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells.
  
  
  CONCLUSIONS
  We demonstrate 1) the time course of NMDAR maturation is cell-type specific, and 2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2-knockout mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-based therapies targeting NMDAR subunit composition on PV cells may provide novel treatments for Rett syndrome.
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School; Lurie Center for Autism, Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Susanna B
authors.initials: SB
authors.lastname: Mierau
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School.
authors.forename: Annarita
authors.initials: A
authors.lastname: Patrizi
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School; Center for Brain Science, Harvard University, Cambridge, Massachusetts.
authors.forename: Takao K
authors.initials: TK
authors.lastname: Hensch
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School. Electronic address: michela.fagiolini@childrens.harvard.edu.
authors.forename: Michela
authors.initials: M
authors.lastname: Fagiolini
mesh_terms: D000818:Animals; D005260:Female; D007395:Interneurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010320:Parvalbumins / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D014793:Visual Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D010320:Parvalbumins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C497393:Mecp2 protein, mouse
keywords: Development; GluN2A; GluN2B; Parvalbumin; Rett syndrome; Visual cortex