Autism Spectrum Disorders (ASDs) are characterized by problems with social engagement and communication, as well as inappropriate restrictive and repetitive behaviors. It has been reported that as many as 1 in 70 children have been diagnosed with autism; therefore it represents a major health problem that also profoundly impacts a sizeable number of military families. It is known that ASDs have a strong genetic heritability component, but only in a small proportion of cases has the genetic basis been identified, and there is large heterogeneity in the genetic causes. Recently several mutations were identified in individuals with ASDs in genes that code for important Ca2+ channels. These ion channels are known to affect neuronal and synaptic development, and therefore are likely causal to autism diagnosed in these patients. More specifically, because these mutations are known to cause a gain-of-function phenotype, increasing Ca2+ influx through the channel, they provide a unique opportunity to model the disorder in a mouse and establish a “molecules to behavior” understanding of how brain circuits are functionally altered in ASDs. The two partnering laboratories have collaborated to create a novel mutant mouse with the human mutation engineered into the genome. The mice display several aberrant repetitive and social behaviors that are correlates of the altered behaviors in the human disorder. Therefore these mice are potentially valuable models for understanding the alterations in brain activity that underlie ASDs. In this proposal we will use these mice to determine the extent of the alteration in synapses, neural circuits and behavior and ask the following three questions: 1) how does the mutation in this ion channel affect the development of neurons in a region of the brain known to be important for habit? 2) what are the alterations in naturalistic behaviors in these mice that correlate with the symptoms of ASDs, and can we detect this by probing activity of neurons as mouse perform basic behaviors? 3) can we fix the problems in these mice by using drugs that target this ion channel? This proposal directly addresses one of the “Areas of Interest” by assessing novel therapeutics in valid preclinical models. These studies are designed to understand a critical problem in the ASD field, address important knowledge gaps, and ultimately will determine whether we can find ways to rectify the activity in brain circuits that contribute to the altered behaviors in ASDs. Our experimental design will employ cutting-edge techniques to record from neurons in regions of the brain associated with ASDs, and is designed to incorporate the complementary expertise of the partnering laboratories. The ultimate outcome will be in identifying the network basis for repetitive and restricted behaviors, which are a hallmark of ASDs, and will inform the future development of novel treatments.
|Effective start/end date||9/30/18 → 9/29/21|
- U.S. Army Medical Research and Materiel Command (W81XWH-18-1-0778)