Abstract
Activity-dependent neuroprotective protein (ADNP), discovered and first characterized in our laboratory (IG), is vital for mammalian brain formation and presents one of the leading genes mutated de novo causing an autistic syndrome, namely the ADNP syndrome. Furthermore, a unique mouse model of Adnp-haploinsufficiency was developed in the laboratory (IG), with mice exhibiting cognitive and social deficiencies. ADNP is regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP). In this respect, PACAP was independently identified as a sexual divergent master regulator of the stress response. Here, we sought to determine the impact of the Adnp genotype and the efficacy of PACAP pre-treatment when subjecting Adnp+/− mice to stressful conditions. Significant sex differences were observed with Adnp+/− males being more susceptible to stress in the object and social recognition tests, and the females more susceptible in the open field and elevated plus maze tests. Splenic Adnp expression and plasma cortisol levels in mice were correlated with cognition (male mice) and anxiety-related behavior. These findings were further translated to humans, with observed correlations between ADNP expression and stress/cortisol content in a young men cohort. Altogether, our current results may establish ADNP as a marker of stress response.
Highlights
Activity-dependent neuroprotective protein (ADNP), discovered and first characterized in our laboratory (IG) as vital for mammalian brain formation[1,2,3,4,5], was found to be frequently mutated in autism spectrum disorder (ASD) with associated cognitive deficits[6], as well as deficiencies in schizophrenia and Alzheimer’s disease (AD)
As previously observed, non-challenged Adnp+/− mice showed no significant preference for mice over objects[7], and here, this behavior was not altered with stress
In the current study, the aspects of anxiety levels, as well as cognition and social activity were examined in vivo in the unique mouse model of Adnp haploinsufficiency, compared with normal mice exposed to stressful conditions of 48 h of constant bright illumination and solitude
Summary
Activity-dependent neuroprotective protein (ADNP), discovered and first characterized in our laboratory (IG) as vital for mammalian brain formation[1,2,3,4,5], was found to be frequently mutated in autism spectrum disorder (ASD) with associated cognitive deficits[6] ( known as the ADNP syndrome), as well as deficiencies in schizophrenia and Alzheimer’s disease (AD) In this respect, an 8-aminoacid peptide (NAPVSIPQ = NAP, called davunetide or CP201) derived from ADNP, was likewise discovered in the Gozes laboratory, and shown to enhance cognitive function in Adnp+/− mice[4,7,8]. A better understanding of the ADNP syndrome was provided, paving the path for NAP (CP201) to clinical development in the ADNP syndrome children[7]
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