MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex.
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome, an autism spectrum-associated disorder with a host of neurological and sensory symptoms, but the pathogenic mechanisms remain elusive. Neuronal circuits are shaped by experience during critical periods of heightened plasticity. The maturation of cortical GABA inhibitory circuitry, the parvalbumin(+) (PV(+)) fast-spiking interneurons in particular, is a key component that regulates the initiation and termination of the critical period. Using MeCP2-null mice, we examined experience-dependent development of neural circuits in the primary visual cortex. The functional maturation of parvalbumin interneurons was accelerated upon vision onset, as indicated by elevated GABA synthetic enzymes, vesicular GABA transporter, perineuronal nets, and enhanced GABA transmission among PV interneurons. These changes correlated with a precocious onset and closure of critical period and deficient binocular visual function in mature animals. Reduction of GAD67 expression rescued the precocious opening of the critical period, suggesting its major role in MECP2-mediated regulation of experience-driven circuit development. Our results identify molecular changes in a defined cortical cell type and link aberrant developmental trajectory to functional deficits in a model of neuropsychiatric disorder.
Department of Neuroscience, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
Keerthi
K
Krishnan
Department of Neurobiology, Northwestern University, Evanston, IL 60208;
Bor-Shuen
BS
Wang
Department of Neuroscience, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
Jiangteng
J
Lu
Program in Neuroscience, Stony Brook University, Stony Brook, NY 11794.
Lang
L
Wang
Program in Neuroscience, Stony Brook University, Stony Brook, NY 11794.
Arianna
A
Maffei
Department of Neurobiology, Northwestern University, Evanston, IL 60208; huangj@cshl.edu cang@northwestern.edu.
Jianhua
J
Cang
Department of Neuroscience, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; huangj@cshl.edu cang@northwestern.edu.
Z Josh
ZJ
Huang
D000818:Animals; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D014793:Visual Cortex / Q000502:physiology*
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
MeCP2; Rett syndrome; critical period plasticity; parvalbumin interneurons; visual cortex