Nerve cells communicate through finely tuned electrical signals; with too much or too little electrical activity, the brain cannot function normally. This research is focused on how the electrical activity of individual neurons is changed in autism and how that abnormal electrical activity disrupts specific brain circuits to cause the behavioral symptoms associated with autism. By understanding how the electrical circuitry is disrupted in autism, we may be able to develop new treatments for this disorder.
Autism spectrum disorder is a prevalent and devastating neuropsychiatric condition characterized by disabilities in social communication and repetitive, restricted interests and behaviors. Though many genetic changes have been linked to autism, it is unclear how the implicated genes translate into clinical symptoms. In the proposed studies, I will use cutting-edge techniques to discover how diverse genetic causes of autism connect at the level of neuronal circuits to drive autism-associated behaviors. I am a board-certified Child Neurologist with a PhD in Neuroscience. I have extensive training in neurobiology and the clinical evaluation and management of neurological diseases. My long-term goal is to understand the autistic brain through clinically-relevant basic science research. In order to become an independent investigator running my own productive research group elucidating the neurobiology of autism, there are several skills I need to master. Through the proposed research and career development plan, I will obtain the training, mentorship, and experience I need to launch my career as a successful independent investigator. My preliminary studies show a specific deficit in the excitability of prefrontal corticothalamic neurons that is common to three mouse models of autism (Fragile X knockout, CNTNAP2 knockout, and prenatal valproate exposure). Importantly, the social behavior of valproate-exposed mice can be bidirectionally modulated by acute ontogenetic activation or inactivation of these prefrontal corticothalamic neurons. In the proposed studies, I will use these mouse models of autism to test specific hypotheses about how the prefrontal corticothalamic circuit participates in autism-associated behaviors. In Aim 1, I will perform in vitro brain slice electrophysiology to test the hypothesis tat in autism, synaptic transmission is defective between the prefrontal cortex and thalamus. In Aim 2, I will perform in vivo electrophysiology and in vivo calcium imaging of the prefrontal cortex and thalamus during social behavior to determine how these regions interact in the normal and autistic brain. Finally, in Aim 3, I will perform ontogenetic manipulations in awake, behaving mice to test how the prefrontal corticothalamic circuit directly contributes to social behavior. I have assembled a stellar team of experts in neurobiology and autism to serve as mentors - Drs. Vikaas Sohal, Mattew State, and Elysa Marco. Two other world-renown experts will serve as advisors for the in vivo electrophysiology (Dr. Loren Frank) and behavioral experiments (Dr. Jacqueline Crawley). I will supplement the mentored research with coursework on signal processing, data analysis, computer programming, biostatistics, and bioethics. I will gain expertise in the clinical aspects of autism spectrum disorder through mentoring by Drs. State and Marco. Finally, I will hone my professional skills by publishing original research manuscripts, presenting my work at international meetings, and participating in formal courses on scientific leadership and management. By the completion of the career development award, I will have successfully applied for R01-level funding. As a result of the individually-tailored carer development plan, I will be able to launch my career as a physician- scientist and independent investigator leading a productive team of researchers focused on discovering the cellular and circuit-based mechanisms of autism spectrum disorder.