PHENOTYPING REGRESSION IN A FEMALE MOUSE MODEL FOR RETT SYNDROME USING COMPUTATIONAL NEUROETHOLOGY TOOLS

Regression is defined as loss of acquired skills over time and is a key feature of many neurodevelopmental disorders such as Rett syndrome (RTT). RTT is caused by mutations in the X-linked gene Methyl CpG-Binding Protein 2 (MECP2) and is characterized by a period of typical development with subsequent regression of previously acquired motor and speech skills in girls. In human and animal models, it is clear syndromic phenotypes are dynamic over time but phenotyping regression over time in animal models has remained elusive. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female RTT mouse models is a major contributing factor. Thus, systematic characterization of etiologically relevant behaviors in female Mecp2^heterozygous (Het) mouse models are needed to move forward. We established an ethologically relevant alloparental pup retrieval task as a model to study cellular mechanisms of complex sensorimotor skills. New deep learning approaches for computational ethology allow for robust analysis of complex behaviors to model endophenotypes and investigate the underlying cellular mechanism in animal pre-clinical models. Using systematic characterization of behavior and histological analysis, we observe adolescent Het have typical perineuronal nets (PNN) in the sensory cortex, mild tactile deficits, and perform efficient pup retrieval. In contrast, adult Het show increased PNN, tactile sensory deficits, and are inefficient at pup retrieval. Using deep learning, we tracked the mice and performed multidimensional analysis on pup retrieval trajectories. Multidimensional analysis revealed two groups of Het: Het that behave like WT, and Het that regress over trials. Surgical degradation of PNNs in the sensory cortex did not rescue behavioral phenotypes in adult Het. We also observe a cell type specific increase in MECP2 expression in adolescent Het, but not adult Het. We speculate the precocious cell type specific increase in MeCP2 expression in adolescent Het may provide compensatory benefits, while the inability to further increase MeCP2 levels leads to regression in adulthood. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which has implications for better designing experimental therapeutics.