In my Ph.D., I investigated how gene mutations associated with autism spectrum disorder (ASD) affect brain function, with a focus on synaptic transmission. My studies focused on the prefrontal cortex (PFC) - a brain area important for sociability and other advanced cognitive functions. For a detailed summary on PFC and its role in various disorders, please see our recent review article (Yan & Rein, Molecular Psychiatry, 2021).
On chromosome 16, there is a stretch of DNA comprising 27 genes which is called 16p11.2. This region can be randomly duplicated or deleted, resulting in either too much or too little of these genes. People with either deletion or duplication of the 16p11.2 region are at increased risk for ASD, intellectual disability, epilepsy, and many other developmental disorders. For a detailed summary, see (Rein & Yan, Trends in Neurosciences, 2020). These genetic mutations are fairly prominent, each affecting ~1 in every 3,500 individuals, though very little had previously been known about how they affect the brain. Through our studies, we discovered that neurons in the PFC are less active in mice with 16p11.2 deletion (Wang & Rein, Journal of Neuroscience, 2018), and more active in mice with 16p11.2 duplication (Rein et al., Molecular Psychiatry, 2020). Moreover, leveling out the activity of these PFC cells improved sociability and cognition in both mouse models! Our findings suggests that imbalanced activity of PFC neurons is a core mechanism driving social and cognitive deficits in 16p11.2 deletions & duplications.
As a scientist working with animal models of autism, I believe we must challenge and improve the depth of our behavioral tests for modeling the complex features of ASD. While working in my Ph.D., I discovered a concerning problem in the scientific literature: a common method for testing social behavior in mice was producing highly inconsistent results across different research labs. We therefore developed a standardized protocol of this test with robust sensitivity to social deficits across multiple autism mouse models (Rein et al., Nature Protocols, 2020). I also led the development of a behavioral tool that can be used to assess social motivation in ASD mouse models (Rein et al., Genes, Brain and Behavior, 2019). With these approaches, I hope we may more thoroughly investigate social behavior, and better identify how animal models of psychiatric disease recapitulate (and fail to recapitulate) the various facets of these complex disorders.