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.
Autism is clearly a spectrum of disorders in which around half of the cases are associated with a specific genetic mutation. However, no more than 2% of all cases are caused by any one mutation. Autism-associated mutations modeled in the mouse brain cause defects in morphological development and synaptic connectivity of neurons. Thus, regulation of neuronal growth and sculpting of synaptic connectivity may underly the development of cognitive and affective behaviors that are altered in autism. We know that growth factors and related signaling pathways modulate neuronal growth through the regulation of translation and cytoskeletal remodeling. While we have learned a great deal about these pathways and the regulation of translation through the context of autism research, the dysregulation of cytoskeletal dynamics in the context of autism is largely unexplored. In this project we have used a bioinformatic approach to predict whether gene mutations found in patients with autism will directly regulate cytoskeletal proteins. We are now using our retroviral CRISPR system to examine the morphological impact of the genes that likely impact the cytoskeleton. For genes having an impact in this somatic cell screen, we are implementing CRISPR in mouse zygotes to generate novel whole-animal models for autism.
Bryan W. Luikart, PhD
Department of Molecular and Systems Biology
Geisel School of Medicine at Dartmouth