Research Department: Neurology Graduation Date: May 2019
Abstract: In the United States, 1 in 68 children are diagnosed with Autism Spectrum Disorder (ASD) which is characterized by symptoms such as abnormal social interaction, problems with communication, disruptions in executive functions, and delayed learning of language. Due to the nature of cognitive developmental disorders, it is important to determine the genetic basis and possible causation of ASD and how specific genes can affect specific brain regions, such as the hippocampus. The hippocampus is a major brain region associated with learning, and recent research suggests that the hippocampus also has a part in social memory and regulating autistic symptoms. Hippocampal synaptic transmission is reduced via the RhoA pathway in Kctd13 knockout mice, which is a gene inside of an ASD-related chromosomal segment, 16p11.2. Interestingly, Kctd13 is an adapter protein for the ubiquitin-ligase Cul3, which has been characterized as a high-risk Autism gene through genome-wide association studies. For this study, we utilized a heterozygousCul3mouse model to determine its role in hippocampal function and impact on social behavior.Cul3heterozygous mice have a ~50% reduction of Cul3 protein and display no differences in general behaviors or weight. Using a 3-choice box behavioral test, we found reducing Cul3 expression resulted in mice spending less time in the zone of a novel mouse compared to a familiar mouse, while wild-type littermates displayed the opposite. This finding suggests possible resistance to change or avoidance of unfamiliar social environments. Other findings related to the reduction of Cul3 were lowered basal synaptic transmission corresponding with elevations in RhoA protein levels, which can lead to loss of spines, spine shrinkage and neurite retraction. Spine analysis performed with Neurolucida 360 revealed no differences in CA1 pyramidal spine density between Cul3 heterozygous mice and wild-type littermates, so further studies are necessary to reveal the underlying cause of differences in synaptic transmission. It was also observed that RhoA protein levels are significantly increased around postnatal day 15, indicating the early postnatal development as a susceptible time point for development of ASD. Overall, these data suggest that reduced hippocampal synaptic transmission, possibly via the RhoA pathway, may contribute to the development of Autistic symptoms and behavior.
What does research mean to you? Research means being dedicated to finding the answer to an important question, while remaining open to failure and change of direction.
Tell us about your journey. I enrolled at UT Dallas with a passion for psychology and a goal to help those addicted to substances. I was introduced to research in psychology as a freshman when I started as a Research Assistant for the Online Social Influence Lab, which is a hybrid human subject’s lab that works both with Behavioral and Brain Sciences as well as the ATEC program. In this lab, personality, preferences and biases related to social media, mobile games and other web-based communication were probed in the undergraduate UTD population. In the summer after my freshman year, I joined the Filbey Lab at the Center for BrainHealth UTD. As an intern working in Filbey’s lab, I recruited participants for various observational marijuana studies that were being conducted. These studies included methods such as personality batteries, memory and IQ tests, fMRI scans and administering transcranial magnetic stimulation to both marijuana users and non-users. As my junior year approached, I applied for the Green Fellowship and was paired in Dr. Powell’s research lab in UTSW Biomedical Research Center. Dr. Powell’s neurology lab conducts research to find genetic contributors and factors of Autism. These studies are done using mouse models in which genetic mutations, that have been found to be related to Autism, are induced. The tests and studies are done to detect biochemical, physiological and behavioral differences in the mutated mice and “wild-type” or non-mutated mice.
Advice for Future Green Fellows
Trust yourself and your abilities, specifically your abilities to learn and adapt. It is easy to feel overwhelmed: especially in a new environment, with a new schedule, and perhaps with no previous training in some of the procedures and experiments you will be required to do in your lab. It is important to ask questions and let your mentor know if you are confused or need guidance on what can be done to help you succeed. Once you are confident about what you are doing, your preparation, experiment and analyses will become like second nature. It is also important to have a better understanding of the “big picture” and how your day to day experiments factor into answering the research project question/hypothesis.