Rett Syndrome (RTT) is diagnosed as a neurodevelopmental disorder, characterized by partial or complete loss of acquired spoken language, acquired motor skills and stereotypic hand movements. Mutations in X-linked gene methyl CpG-binding protein 2 (MECP2), a chromatin remodeler and gene regulator, is the causative gene for typical RTT. RTT is hypothesized to be the result of altered synaptic connectivity and plasticity caused by abnormal experience-dependent synapse development and maintenance. However, few experimental paradigms have explored how synaptic plasticity in RTT is affected over time and physiological changes with cellular, circuit and behavioral level granularity. Using Mecp2-null and heterozygous mouse models, we have previously shown that MECP2 regulates the timing of experience-dependent plasticity in the adult auditory cortex in a learned maternal behavior paradigm. We found that Mecp2-heterozygous females (SurHet) were inefficient gatherers, likely due to atypical auditory perception, caused by an abnormal, transient increase in numbers of mature perineuronal nets (PNNs). PNNs are extracellular matrix structures that act as physical barriers for plasticity, and form predominantly around cortical parvalbumin GABAergic neurons. Major questions remain: Pup retrieval behavior is a complex sequence of events involving auditory, tactile, olfactory senses and goal-directed motor events. How do different sensory inputs (pup vocalizations, feel and smell of pups) contribute to the motor outputs (adult vocalizations, goal-directed search and carrying pups by mouth to the nest)? Our aims in this R15 proposal are to (1) characterize vocalizations/syllables and interactions between pups and adult females during pup gathering task, using integrated analysis of audio and video recordings with new machine learning algorithms; (2) identify the time line of altered PNN expression in piriform cortex, a brain region thought to be important for olfactory coding and a relay station for multisensory integration using immunostaining/imaging and then, surgical manipulations of piriform cortex. We hypothesize that expression of mature PNNs in the piriform cortex is regulated by MECP2 and contribute to proper integration and functioning of distinct components of pup retrieval behavior. The results from this study aims to identify novel circuits and mechanisms involved in multisensory integration of vocal communication during complex social behavior, which are one of the most striking yet underexplored phenotypes in RTT. Relevance to health: Rett Syndrome is diagnosed as a neurodevelopmental disorder with sensory, motor and social impairments; however, it is currently unknown where and how these impairments develop and change over time in adulthood. This proposal aims to understand how plasticity, the ability of the brain to incorporate and adapt to changes in its environment and surroundings, is affected by mutated genes in RTT and associated neurological disorders.
Rett syndrome is a neurological disorder caused by mutations in methyl-CpG-binding protein 2 (MeCP2). The overall goal is to determine how MECP2 deficiency results in altered experience-dependent plasticity, critical for learning and navigating one's social environment, and to observed stereotypic RTT phenotypes.
