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MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex.

ABSTRACT: 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.

SUBMITTER: Krishnan K

PROVIDER: S-EPMC4553776 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundIn cat visual cortex, critical period neuronal plasticity is minimal until approximately 3 postnatal weeks, peaks at 5 weeks, gradually declines to low levels at 20 weeks, and disappears by 1 year of age. Dark rearing slows the entire time course of this critical period, such that at 5 weeks of age, normal cats are more plastic than dark reared cats, whereas at 20 weeks, dark reared cats are more plastic. Thus, a stringent criterion for identifying genes that are important for plasticity in visual cortex is that they show differences in expression between normal and dark reared that are of opposite direction in young versus older animals.ResultsThe present study reports the identification by differential display PCR of a novel gene, α-chimaerin, as a candidate visual cortex critical period plasticity gene that showed bidirectional regulation of expression due to age and dark rearing. Northern blotting confirmed the bidirectional expression and 5'RACE sequencing identified the gene. There are two alternatively-spliced α-chimaerin isoforms: α1 and α2. Western blotting extended the evidence for bidirectional regulation of visual cortex α-chimaerin isoform expression to protein in cats and mice. α1- and α2-Chimaerin were elevated in dark reared compared to normal visual cortex at the peak of the normal critical period and in normal compared to dark reared visual cortex at the nadir of the normal critical period. Analysis of variance showed a significant interaction in both cats and mice for both α-chimaerin isoforms, indicating that the effect of dark rearing depended on age. This differential expression was not found in frontal cortex.ConclusionsChimaerins are RhoGTPase-activating proteins that are EphA4 effectors and have been implicated in a number of processes including growth cone collapse, axon guidance, dendritic spine development and the formation of corticospinal motor circuits. The present results identify α-chimaerin as a candidate molecule for a role in the postnatal critical period of visual cortical plasticity.

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MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex.

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