PACAP, VIP, and ADNP: Autism and Schizophrenia

Abstract

Thirty years ago we cloned the gene for vasoactive intestinal peptide {(VIP),} coding for a major brain neuropeptide. We have also established the first {VIP} transgenic mice as well as then novel {VIP} agonists and antagonists leading to the discoveries of {VIP} functions in brain development, learning and memory as well as social interactions. Fifteen years ago we discovered activity-dependent neuroprotective protein {(ADNP),} as a {VIP} regulated protein, and showed that it is essential for brain formation/function. Follow-up studies identified pituitary adenylate cyclase activating polypeptide {(PACAP)} also as an {ADNP} regulating neuropeptide. We have further identified {ADNP} as a member of the chromatin remodeling complex, {SWI/SNF} also associated with alternative splicing of tau and prediction of tauopathy. In neurons, {ADNP} is found in the nucleus as well as in the neuronal processed. We have identified cytoplasmic {ADNP} interactions with the autophagy regulating microtubule-associated protein 1 light chain 3 {(LC3)} and with microtubule end binding {(EB)} proteins. The {ADNP-EB-binding} {Ser-Ile-Pro} {(SIP)} domain is shared with the {ADNP} snippet drug candidate, {NAPVSIPQ} termed {NAP} (davunetide). Recently, multiple mutations in {ADNP} were found in children defined within the autism spectrum and exhibiting cognitive dysfunctions. Better understanding of {VIP-ADNP} interactions should shade light on brain development and function toward better management of the autism spectrum disorders {(ASDs).} Our further findings indicated dysregulation in the autophagy pathway in schizophrenia, coupled to {ADNP} dysregulation and amelioration by {NAP} (davunetide treatment).