Rett syndrome (RTT) is a broad-ranging neurological disorder caused primarily by mutations in the X-linked methyl CpG-binding protein 2 (MECP2), a transcriptional regulator that binds methylated DNA. In females, the typical Rett syndrome appears following a period of apparently normal development and achievement of early milestones, only to lead to a rapid loss of acquired language and manual skills by the second year of life and the development of ataxia, respiratory dysrthythmias, seizures, and autistic features such as loss of eye contact. Mutations that would cause typical RTT in females produce a much more severe phenotype in human males (neonatal encephalopathy and death within the first years of life);milder mutations can lead to early- onset bipolar disorder or schizophrenia with motor abnormalities and obesity. Although the precise functions of MeCP2 protein continue to be debated, a number of mouse models have provided information about the origins of various phenotypes. Male Mecp2 nulls (most studies have used male mice to avoid the confounding influence of X chromosome inactivation on phenotypes), develop a severe RTT-like phenotype and die within the first four months of life. Most intriguing, however, have been studies examining the effect of deleting Mecp2 in specific neuronal groups: the Zoghbi lab discovered that loss of Mecp2 in GABAergic neurons captures the majority of RTT phenotypes-ataxia, stereotypies, breathing dysrhythmias, and learning and memory deficits. This result is all the more striking in light of the fact that GABAergic neurons account for only one-fifth of the brain's neuronal population, and loss of Mecp2 in these cells reduces GABA signaling by only ~30-40%. The Zoghbi lab proposed that partial reduction in GABA signaling mediates the phenotypes of these mice, possibly by perturbing the balance between excitatory and inhibitory signaling Alterations in this balance are suspected to underlie many other neuropsychiatric disorders, including schizophrenia, autism, obsessive-compulsive and anxiety disorders-all within the spectrum of phenotypes produced by MECP2 mutations. Given that Rett symptoms in the most severely compromised mice (male Mecp2 nulls) can be rescued by reactivation of Mecp2 in all neurons, I propose to test the hypothesis that rescue of Mecp2 deletion in GABAergic neurons is sufficient to reverse Rett-like symptoms in both male and female Mecp2 mutant mice by normalizing GABA signaling and improving excitatory/inhibitory balance. We recently conducted a pilot study in which we re-expressed Mecp2 in the GABAergic neurons of male Mecp2 null animals. We found significant rescue of body weight, ataxia, and grip strength (a readout of fine motor control). This suggests that the GABAergic circuitry not only plays a critical role in the pathogenesis of the disorder but is also a promising target for therapies for Rett syndrome patients. I propose to rescue GABA signaling by genetic and pharmacological means to lay the groundwork for future clinical studies.
Although MECP2, whose mutation underlies Rett Syndrome (RTT), is expressed broadly, recent studies have shown that deletion of the gene in just GABAergic neurons reproduces most phenotypic aspects of the syndrome. The project will test the hypothesis that improving GABA signaling in the brain could mitigate features of RTT;if successful, these findings can be rapidly translated to treat individuals with RTT.