Projects: The overall goal of my research is to understand how genes influence behavior and how genetic variants predispose to neurodevelopmental and neuropsychiatric disorders.

Identification of regulators of MeCP2 abundance. Mutations of MeCP2 cause Rett syndrome, a neurodegenerative disorder that typically manifests in girls with neurodevelopmental regression at one to two years of age. Duplications of the genomic region, including the MeCP2 gene, cause MeCP2 duplication syndrome, a disorder that manifests in boys with mental retardation, recurrent respiratory infections and autistic features. Interestingly, both Rett syndrome  (a condition caused by defective MeCP2) and MeCP2 duplication syndrome (a condition of excessive MeCP2 expression) have several common features, including stereotypic hand movements, anxiety and social avoidance. In a cell-based assay, we are trying to identify regulators of MeCP2 abundance, which may represent therapeutic targets for MECP2 duplication syndrome.

MeCP2 and the cholinergic nervous system. The cholinergic system is a modulatory neurotransmitter system of utmost importance when it comes to activities that depend on selective attention and conscious awareness. Regional deficits in the cholinergic system have been associated with alterations in consciousness in several neurodegenerative diseases. In a mouse model for Rett syndrome, generated by truncating MeCP2 at amino acid 308, MeCP2308/Y mice display memory and learning deficits. By creating a conditional knockout of MeCP2 in cholinergic neurons, I am trying determine to which extent this phenotype is caused by deficiency of MeCP2 in cholinergic neurons.

Copy number variants (CNVs) of CHRNA7. The CHRNA7 gene codes for the alpha7 subunit of the nicotinic acetylcholine receptor. CNVs of this gene predispose to neuropsychiatric phenotypes. We are studying the clinical phenotypes of CHRNA7 deletions and duplications, and how these may affect sensory gaiting in humans. A placebo-controlled treatment trial will investigate if some of that phenotype is amenable to treatment.