The Role of MeCP2 in Brain Development and Neurodevelopmental Disorders

Abstract

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Rett syndrome, the primary disorder caused by mutations in the X-linked MECP2 gene, is characterized by a period of cognitive decline and development of hand stereotypies and seizures following an apparently normal early infancy. In addition, MECP2 mutations and duplications are observed in a spectrum of neurodevelopmental disorders, including severe neonatal encephalopathy, X-linked mental retardation, and autism, implicating MeCP2 as an essential regulator of postnatal brain development. In this review, we compare the mutation types and inheritance patterns of the human disorders associated with MECP2. In addition, we summarize the current understanding of MeCP2 as a central epigenetic regulator of activity-dependent synaptic maturation. As MeCP2 occupies a central role in the pathogenesis of multiple neurodevelopmental disorders, continued investigation into MeCP2 function and regulatory pathways may show promise for developing broad-spectrum therapies.

A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice

“…Although neural network hyper-excitability is a major co-morbidity of Rett syndrome patients (Huppke et al, 2007), and also present in other conditions displaying errant MeCP2 expression (Gonzales and LaSalle, 2010), how impaired MeCP2 function leads to hyper-excitable neural circuits remains poorly understood. Using MeCP2-deficient mice as model systems and cortical epileptiform discharges as an index of network hyper-excitability, our results implicate enhanced GABAergic signaling as a contributing factor for the cortical discharge phenotype of MeCP2-deficient mice.…”

“…In this regard, relatively subtle decreases in MeCP2 expression are sufficient to induce behavioral impairments in mice (Samaco et al, 2008;Kerr et al, 2008), and decreases in brain MeCP2 levels have been reported in neurological conditions such as Angelman syndrome, attention deficit hyperactivity disorder, and general autism (Nagarajan et al, 2006;Neul, 2012;Gonzales and LaSalle, 2010). Thus, the neural link we illustrate here between MeCP2 and GAT-1 expression may be worthy of assessment in other conditions in which imbalances of excitatory and inhibitory tone are believed to have a role in pathogenesis.…”

Epigenetic epidemiology in psychiatry: A translational neuroscience perspective

“…Given the essential role of Mthfr in brain function and neurodevelopment [196,197], and the fact that family and twin studies have established considerable shared genetic variance between psychiatric disorders [198][199][200], a recent meta-analysis (on a total of more than 29,000 subjects) tested whether genetic variation in Mthfr contributes to the shared genetic vulnerability of schizophrenia, bipolar disorder and unipolar depressive disorder [201]. This meta-analysis showed that Mthfr C677T was significantly associated with the combined group of schizophrenia, bipolar disorder and unipolar depressive disorder (odds ratio = [202]. Besides being the major cause of Rett syndrome (a rare but fulminant neurodevelopmental disorder in young girls) [203], mutations in this X-linked gene have been found to be associated with a broad array of other neurodevelopmental disorders in males and females, including X-linked mental retardation [204,205], severe neonatal encephalopathy, Angelman's syndrome, and autism [202].…”

Autism and Genetic Syndromes

“…This stagnation of development also becomes manifest in a retarded and disproportionate growth in head circumference, decrease of eye contact, and both cognitive and motor deterioration. Already in the first year of life, autistic behavioural elements are present such as social withdrawal, declining speech and communication, limited eye contact, grinding of the teeth, and characteristic hand stereotypies (Ben Zeev, 2007;Gonzales & LaSalle, 2010). In the majority of the patients, the syndrome is associated with severe epilepsy.…”