Rett Syndrome (RTT) is an autism spectrum disorder that affects approximately 1 in 20,000 girls and is caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2). The cholinergic system appears to be particularly important in RTT, as decreases in cholinergic markers have been correlated with increased clinical severity in patients with RTT. Schaaf and Zoghbi have developed a powerful transgenic mouse model, whereby MeCP2 is selectively deleted in cholinergic neurons only, to facilitate study of the contribution of this cholinergic lesion to the overall phenotype of RTT. Interestingly this model exhibits a selective deficit in recognition memory, a form of declarative memory that has been shown by lesion and electrophysiological studies to be dependent upon cholinergic signaling in the perirhinal cortex (PRH). This memory deficit may map onto the intellectual disability seen in patients with RTT, however, its molecular and electrophysiological underpinnings are unknown. This study will use qPCR, immunoblot and stereological techniques to investigate cell specific perturbations of the circuit that underlie the memory defict seen in selective cholinergic MeCP2 knock-out mice. Optogenetic and in vivo electrophysiological approaches will be used to investigate circuit level disruptions of the behavioral deficit. These measures will be included with behavioral metrics of recognition memory in regression models to determine the relative contribution of cellular and physiological phenotypes to behavioral impairments in the context of cholinergic MeCP2 knock out. These experiments will provide new information about the contribution of the cholinergic system to the trajectory of Rett Syndrome. Better understanding of this trajectory will help in the development of targeted treatments for specific aspects of the syndrome.
Rett Syndrome (RTT) is a devastating neurodevelopmental disorder affecting approximately 1 in 20,000 girls for which there is currently no cure and no targeted treatments. This dearth of targeted treatments is attributable, in part, to the lack of information regarding what specific neuronal circuits and neurotransmitter systems underlie different aspects of the broad RTT syndrome phenotype. The goal of this study is to determine the contribution of cholinergic circuitry to the trajectory of RTT, thus potentially informing the future development of such targeted treatments.
| Jiang, Li; Kundu, Srikanya; Lederman, James D et al. (2016) Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits. Neuron 90:1057-70 |
