Josh Huang Ph.D.

Abstract

• Cellular and molecular alterations in GABAergic inhibitory circuits by mutations in MeCP2, a gene implicated in the Rett syndrome of the autism spectrum disorders

  Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X chromosome-linked gene methyl-CpG-binding protein 2 (MeCP2), but the underlying pathogenic mechanisms remain mysterious. It is estimated that one in every 10,000-15,000 females develop RTT, but the overall prevalence of MeCP2 mutations in the population is unknown. RTT is hypothesized to result from inappropriate neuronal connectivity and communication, possibly through abnormal experience-dependent maturation, refinement, and maintenance of neural circuits. Neural circuits consist of excitatory and inhibitory neurons. Major efforts have been directed towards studying the glutamatergic excitatory neurons in RTT; but the impact of MeCP2 mutations on the maturation and plasticity of GABAergic inhibitory circuits is almost entirely unknown. We will use mouse models of RTT to discover the pathogenic mechanisms of MeCP2 mutations on development and function of the inhibitory circuits, combining genetic, genomic, imaging, and physiological approaches. We will use genetic engineering to generate "reporter" mouse strains, in which the effects of MeCP2 mutations on inhibitory neural circuits can be visualized and mapped at cellular resolution by imaging technology. In addition, we will identify the molecular targets of MeCP2 in different classes of inhibitory neurons. Furthermore, we will determine the precise morphological and physiological consequences of MeCP2 mutations on inhibitory neurons and circuits. Our studies have implications not only in the pathogenic mechanism of RTT, but also in its diagnosis and treatment.

Institution

• Cold Spring Harbor Laboratory