Preclinical Research

The Autism Genetics Program at the Seaver Autism Center for Research and Treatment represents a centralized initiative in autism genetics. This initiative currently includes the molecular genetics and functional genetics of the Laboratory of Molecular Neuropsychiatry. Most recently, it also includes the clinical genetics collaboration between the Laboratory of Molecular Neuropsychiatry, the Autism Clinical Program, the Autism Assessment Program, and the Department of Genetics and Genome Sciences

Our Center uses state-of-the-art molecular genetic approaches to identify additional genetic causes of autism, making use of detailed behavioral and medical assessments provided by the Autism Assessment Program.

Our Center is a preeminent site for functional genetics linking genetic causes for autism and related conditions to underlying changes in brain function. These approaches are leading to new interventions in autism and related conditions.

Because identifying causal variants in autism immediately leads to animal models and new conceptualization of causes of autism and related conditions, we are expanding our animal and molecular neurobiological studies of genes in autism. Our Center has already supported the development of eight mouse models that illustrate different aspects of autism, as a means of deepening our understanding of pathogenic mechanisms in autism and evaluating therapeutics.

At our Center, researchers are characterizing mouse and rat models with mutations in several autism spectrum disorder (ASD) risk genes, including SHANK3, FMR1, MECP2, and CYFIP1. These studies provide objective measures of the biological effects of the loss of these genes on nerve cell connectivity, strength of the communication between nerve cells (synaptic plasticity), and cognitive, motor, and social behavior. Using this approach, we discovered that treatment of SHANK3-deficient mice with Insulin-Like Growth Factor-1 (IGF-1) ameliorates some synaptic plasticity and motor deficits. These findings have led to clinical trials testing the effects of IGF-1 in individuals carrying mutations in SHANK3.

Our most recent efforts are focused on rat models for ASD. Compared to mice, rats have additional advantages, such as more complex and humanlike neural circuitry and behavioral repertoire. Use of these models will help lead to a better understanding of the deficits in brain areas relevant to ASD and the development of new therapeutic approaches. Our Center’s researchers are characterizing the first rat model carrying a mutation in SHANK3. Similar to the SHANK3-deficient mouse, the rat model displays synaptic plasticity deficits. It also exhibits attentional and social behavior deficits, recapitulating the neuropsychiatric features of Phelan-McDermid syndrome (PMS). Using this model, we have identified further medicines that are now being carried over to clinical trials in patients with PMS.

Seaver Center researchers develop the use of stem cells in autism research. This model system is important for ASD because it allows us to study human nerve cell function in the context of autism genetic variation. In addition, stem cells can be used for gene discovery, employing methods of systems genetics to look for disrupted molecular pathways for treatment targets. Lastly, stem cells can form the basis for intermediate- and high-throughput small molecular screening for new ASD medicines. To date, we have collected more than 250 samples from more than 80 families for stem cell research.