New Insights into Autism Spectrum Disorder
Autism Spectrum Disorder (ASD) comprises a group of developmental disorders characterized by a wide range of symptoms, typically including impaired social interactions and excessive repetitive behaviors. Increasing evidence suggests that the pathophysiology of ASD involves an imbalance between two neuronal pathways, which are composed of direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). These pathways, located in a brain region known as the striatum, work in concert with each other to control behavior by facilitating appropriate motor actions while suppressing inappropriate ones to achieve a particular behavioral task. Activity in these pathways is driven by excitatory synaptic input from brain regions that control emotion, cognition, sensation, and motor function, and a delicate balance of dMSN and iMSN activation is maintained in-part by endocannabinoids (eCBs), which prevent overactivation through negative feedback loops. Correlations between abnormal striatal eCB signaling and ASD behavioral phenotypes have been recently reported in some ASD mouse models. However, a causative relationship between eCB deficiency and ASD behavior has not been previously demonstrated. Research Instructor Brian Shonesy, in the lab of Vanderbilt Basic Sciences Investigator Roger Colbran, hypothesized that impaired eCB signaling may result in excessive excitatory synaptic input to dMSNs, contributing to ASD-associated behavioral symptoms. To test his hypothesis, he created genetically engineered mice that enabled him to selectively and conditionally knockout diacylglycerol lipase alpha (DGLα) in either dMSNs or iMSNs. DGLα is the enzyme that synthesizes the major endocannabinoid, 2-arachidonoylglycerol (2-AG), in the brain. Biochemical characterization demonstrated that DGLα knockout in dMSNs but not iMSNs reduced the total amount of 2-AG in the striatum. Electrophysiological studies revealed that DGLα knockout in dMSNs resulted in increased levels of excitatory synaptic activity. The conditional deletion of DGLα in dMSNs, but not iMSNs, led to impaired sociability and repetitive behavior in the form of excessive grooming. A further modification of the mouse model enabled the researchers to examine the effects of localized DGLα knockout in either the dorsal or ventral striatum. These experiments revealed that DGLα deficiency in the dorsal striatum was associated with impaired sociability, whereas knockout in the ventral striatum led to repetitive behavior. The findings support the hypothesis that eCB signaling in the striatum plays a role in the pathophysiology of some ASD-related symptoms and points to specific cells and regions of the striatum that may be involved. These new insights pave the way for a better understanding of the neurophysiological foundation of ASD and possible new approaches to the treat some behavioral aspects associated with the condition. The research was supported in part by a Vanderbilt Kennedy Center Hobbs Award and a K01 career development award to Dr. Shonesy. Experiments were carried out in collaboration with investigators from the laboratories of Danny Winder and Sachin Patel (Vanderbilt) in addition to David Lovinger (NIAAA) and Ken Mackie (Indiana University). The work is published in the journal Biological Psychiatry [B. C. Shonesy, et al. Biological Psychiatry, (2017) published online Dec. 28, DOI: 10.10.1016/j.biopsych.2017.11.036