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).