Pathogenic variants in the gene MYT1L have been associated with intellectual disability, and autism spectrum condition in exome studies. To study the function of MYT1L and its influence on clinically-relevant behavioral circuits, in collaboration with the Dougherty lab we generated a haploinsufficient mouse model that mirrors a patient-specific mutation (Chen et al., Neuron, 2021). Using this model, the Dougherty lab identified disrupted gene expression, precocious neuronal differentiation as a mechanism for microcephaly, and failure of transcriptional and chromatin maturation in adults. We found this model recapitulated many clinical phenotypes including hypotonia, ASD-related social challenges, ADHD-related hyperactivity, motor coordination issues, and obesity-related weight gain. We are now using a newly validated MYT1L conditional model to temporally and spatially restrict MYT1L loss to understand more directly how this transcription factor influences behavioral circuits.

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Neurofibromatosis Type 1 (NF1) and Autism Spectrum Disorder (ASD) display a significant degree of comorbidity, with approximately 25% of children diagnosed with NF1 exhibiting ASD, while an additional 20% showcase partial ASD features. Despite the confirmed designation of the NF1 gene as a quantitative trait locus for ASD, the untapped potential of utilizing NF1 as a single-gene model for ASD and its capacity to offer in-depth mechanistic insights persist as areas requiring further exploration. Interestingly, individuals with NF1 harboring 3’-end germline NF1 mutations present an elevated burden of autism symptoms in comparison to their counterparts with 5’-end germline NF1 mutations, suggesting a genotype-phenotype correlation. Harnessing this knowledge within experimental models has the potential to unravel predictive biomarkers and elucidate etiologic mechanisms associated with ASD symptomatology. Although mouse models featuring mutations in the homologue of the human NF1 gene (Nf1) have proven instrumental in deciphering non-ASD aspects of the disease, such as tumorigenesis and cognitive impairments, their comprehensive utility in exploring the role of NF1 mutation in ASD remains underexplored. In collaboration with the Gutmann Lab and Wash U NF Center, we are leveraging precision mouse lines with patient-specific genetic variation introduced into the Nf1 gene to understand how these mutations lead to ASD-relavant consequences, the potential role of mutation location, as well as the interplay betwen sex and Nf1 haploinsufficiency.

Social Motivation

Preprint: A comprehensive assay of social motivation reveals sex-differential roles of ASC-associated genes and oxytocin

Social motivation, defined as the internal processes that drive these social interactions, has been conceptualized in terms of several interrelated components including social orienting (attending to social stimuli) and social reward seeking (incentive value of social interactions), with each potentially mediated by distinct brain circuits, A focus of my lab is understanding the circuits that drive social motivation, the role of biological sex, and its regulation by genes associated with human conditions like autism spectrum condition (ASC). We developed a novel task to measure social motivation in the mouse leveraging the operant conditioning paradigm. Using this assay, we discovered a more robust level of social motivation in males compared to females, male-biased social motivation changes in models of ASC likelihood, and a female-biased role for the oxytocin system.

Understanding Gait in IDD

We are interesting in understanding the influence of genetic IDD likelihood on motor functions across development, which we feel is an under-researched symptom domain of IDD, especially given the prevalence of motor disruptions, including gait irregularities, in individuals with IDDs like autism spectrum condition and Williams Syndrome. We used the advanced gait analysis system DigiGait to developed a protocol to measure the trajectory of gait components across development (Akula et al., Brain and Behavior, 2020) and identified components of mouse gait that mirror that in human gait. Specifically, developing mice exhibit a trajectory of gait development that establishes ratios of stride components similar to that observed in humans, which can be leveraged to identify sensitive markers of motor impairment. We then applied this protocol to models of IDD likelihood, Nf1 haploinsufficiency and complete deletion of the Williams Syndrome critical region, and found markedly similar spatial, temporal, and postural gait abnormalities during development across the two models (Rahn et al., JNDD, 2021). We are currently working to characterize gait across other models of IDD likelihood to These data will be used to understand how these distinct variants influence the development of gait to provide the foundation for interrogation of convergent neural circuitry pathology. In addition, we want to understand how gait and other motor deficits track with phenotypes representing the core features of specific IDDs to offer a new perspective on NDDs by demonstrating how motor deficits are linked with social and cognitive issues and that they may share common brain underpinnings.

Williams Syndrome Critical Region

Williams Syndrome (WS) is a neurogenetic developmental disorder that results from a loss of a 26 gene locus called the Williams Syndrome Critical Region (WSCR) and is characterized by cardiovascular problems, dysmorphia, cognitive deficits particularly in the visuospatial domain, and other behavioral phenotypes including anxiety and a hypersocial personality. We are interested in understanding the genetic underpinnings of the cognitive and behavioral features of WS, specifically, which genes within the WSCR drive these different features with a focus on the social behaviors. Using a mouse model that is hemizygous for the mouse homologue of the WSCR, called the Complete Deletion Mouse (CD mouse), which recapitulates many WS features observed in humans, we examined how this locus and individual genes therein (i.e. Gtf2i, Gtf2ird1) drove clinically-relevant phenotypes. We identified social communication, motor function including gait, and conditioning deficits in this model, and the roles of Gtf2i and Gtf2ird1 expression (a,b,c), and oxytocin signaling (d) on these phenotypes. Our most recent work revealed enhanced social motivation along with anxiety-like phenotypes, allowing for future genotype-phenotype explorations of the role of individual WSCR genes in these circuits.