UCLA

Autism spectrum disorders (ASD) are a set challenging neurodevelopmental disorders with extremely high prevalence and expensive social cost. There is a good evidence for a genetic contribution to ASD but environment factors also play a role and interact with the genetic loads as a “second-hit” that further exacerbated the syndrome. The later raise the possibility that dysfunctional circadian rhythms may contribute to the disease improving these rhythms may offer a mechanism to help with the management of ASD symptoms. Robust circadian rhythms and good quality of sleep are restorative and critical for many of the same behaviors that are compromised in ASD. However, the possibility that circadian disruption is one of the environmental factors that contribute to the disease has not been well studied. Using the contactin associated protein-like 2 knock out (Cntnap2 KO) mouse model of ASD, this dissertation research addressed this issue by determine whether a mild circadian disruption caused by dim light at night (DLaN) impacts wild type (WT) and Cntnap2 KO mice. In the first study, I demonstrated that the Cntnap2 mutants are vulnerable to DLaN exposure by showing light-evoked disruptions in sleep/wake cycles, the social impairments, and repetitive grooming behavior. Nightly treatment with melatonin was effective in counteracting the negative effects of DLaN. Next, I examined the pathways by which DLaN was detected and specifically explored the role of the photopigment melanopsin in mediating DLaN consequences. The effects of DLaN on circadian behavior, social behavior, and repetitive behavior were prevented in a line of mice in which the cells expressing melanopsin are genetically ablated. In addition, knowing the melanopsin is largely sensitive to light in the blue/green wavelengths, a specialized LED-system was used that minimized the melanopsin activation while still providing illumination for vision. The illumination produced by this lighting system prevented the negative impacts of DLaN. In the third study, I aimed to evaluate the role of inflammation in mediating the effects of DLaN. The Cntnap2 mutation itself was found to alter the immune profiles in the plasma and the prefrontal cortex, and made the mutants even more vulnerable to the DLaN perturbation compared to the WT controls. Moreover, an inhibitor targeting COX-2 signaling effectively blocked DLaN-evoked inflammation as well as the behavioral changes caused by this environmental second hit. Together, this dissertation work supports a model in which DLaN activates inflammatory pathway. Increase in these inflammatory molecules drives behavioral changes. Widely used, inexpensive pharmacological treatments were found to prevent these adverse behavioral changes. Finally, in the last study, a second mouse model of ASD - the fragile X mental retardation 1 (Fmr1) KO mice, was used to test the principle hypothesis that circadian interventions can be beneficial to ASD.