Novel Roles of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and its Receptors in Social Behaviors and Stress Responses in the Mouse

Autism Spectrum Disorder (ASD) is an increasing concern for the world today. The incidence of ASD is steadily increasing every year (currently 1 in 68 U.S. children) but little is known of its etiology (U.S. Center for Disease Control). Research of ASD has centered around the development of mouse models that exhibit all characteristic behaviors of ASD, however those characteristic behaviors are constantly evolving the more we learn about the disorder. It has been proposed that further research of ASD should be directed at single characteristics of ASD in order to find neurobiological treatment targets. We first characterize a social recognition deficit in an mouse lacking the gene for pituitary adenylate cyclase activating polypeptide (PACAP). PACAP is a highly conserved peptide hormone that is required for vasopressin release within the hypothalamus. We then demonstrated the requirement of PACAP in osmotically stimulated vasopressin release. Others have shown that osmotically stimulated vasopressin can improve social recognition by a yet unknown mechanism [69]. Epidemiological studies of ASD have suggested a role for environmental toxins in the etiology of ASD. We demonstrate for the first time that exposure to polybrominated diphenyl ether’s (PBDEs), flame retardants that persist in our environment, cause attenuation of social recognition ability. PBDE exposure also induced changes in plasma vasopressin and aberrant gene expression of both vasopressin and PACAP receptors in the brain. Finally, since increase anxiety and stress is comorbid with ASD, we investigated PACAPs role in psychogenic stress. We demonstrate that the PACAP receptor, vasoactive intestinal peptide receptor 2 (VPAC2r), is required for adrenal catecholamine release in response to psychogenic stress. Acute restraint stress decrease adrenal gene expression of VPAC2r concomitant with increase plasma epinephrine. Additionally, VPAC2r gene deletion attenuates plasma epinephrine release induced by acute restraint stress. These effects of PBDE exposure on PACAP signaling may further our understanding of the etiology of social disorders such as autism