Autism Spectrum Disorder (ASD) is a developmental disorder characterized by symptoms such as altered social interaction, restricted communication, and stereotyped behavior. ASD represents a broad class of disorders that have common features, but no single genetic defect is responsible for all forms of ASD. Mutations in the gene Pten have been found in 5 to 17% of patients with ASD and an enlarged head (macrocephaly). Deletion of Pten in the mouse brain also causes macrocephaly and deficits in social behavior, suggesting that abnormal Pten signaling in neurons may cause this type of ASD. We are currently investigating the functional impact of specific autism-related mutations of Pten on neuronal form and function. We are also examining other genes that may interact with Pten to alter neuronal physiology and synapse formation. We use both in vitro models and in vivo molecular manipulation with viral vectors, whole-cell electrophysiology, and advanced microscopy to test directed hypotheses. Understanding the primary effects of Pten mutations on the function of individual neurons will improve our understanding of the dysfunctional autistic brain. Further, establishing that manipulation of Pten in the mouse can mimic the symptoms of human ASD patients will allow scientists to test treatments that could cure certain forms of ASD.
New neurons are born and functionally integrate into the synaptic circuitry of the adult hippocampal dentate gyrus. Hippocampal neurogenesis is necessary for a normal behavioral response to antidepressant treatments. Thus the molecular mechanisms governing the successful birth and integration of newborn neurons could be exploited to improve treatments for affective disorders. In this project we will explore the impact of microRNAs on adult neurogenesis. MicroRNAs influence the expression of hundreds of genes – potentially regulating gene assemblies important for the birth, differentiation, and integration of newborn neurons. Neuronal activity enhances neurogenesis. Thus, microRNAs that are regulated by activity are potential candidates regulating neurogenesis. We have identified an array of activity dependent microRNAs in a screen of the epileptic mouse dentate gyrus. This project will focus on examining the expression and function of these candidate activity dependent microRNAs. Using lentiviral and retroviral reporters via in vivo stereotaxic surgery we will determine whether a microRNA is expressed at the right place and right time to influence the integration of newborn neurons. Further, we will employ retroviral knockdown of candidate microRNAs to determine whether this has a functional impact on adult neurogenesis.
The Luikart Laboratory
Molecular and Systems Biology
Frank and Myra Weiser Scholar in the Neurosciences
Geisel School of Medicine
74 College Street
Hanover, NH 03755