Gene Deletion of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Reduces Anxiety and Produces Deficits In Social Discrimination In Mice

Background:  

PACAP and its receptors are required for vasopressin (VP)-mediated osmoregulation (Gillard et al, 2007). PACAP has also been implicated in autonomic dysregulation and well as altered anxiety behavior to stress (Hashimoto et al. 2001). Autism spectrum disorders (ASD) are characterized by impaired social interactions, sensory deficits as well as dysregulated neuroendocrine function, and altered anxiety. However, whether PACAP is critical for behaviors relevant to ASD is unclear. 

Objectives:  

The aim of our study is to determine if PACAP gene deletion has aberrant affects on both neuroendocrine function and behaviors relevant to ASD, namely anxiety and social recognition. Using a PACAP gene knockout (KO) model we tested the hypothesis that PACAP gene deletion is critical for anxiety and social behavior. We also measured somatodendritic vasopressin responses in acutely dissected punches taken from the supraoptic nucleus of the same PACAP knockout (KO). Comparisons were made with age-matched wildtype (WT) mice. 

Methods:  

In the present study, PACAP KO mice subjected to 2g% NaCl drinking for 7 d did not show the stimulated VP release evident in wildtype (WT) mice (48.5+4.6 vs. 230.9+52.1% of WT normosmotic, p=0.03, n=11). These data indicate reduced osmotic regulation associated with the lack of PACAP. Central VP release from supraoptic neuroendocrine cells has also been implicated in neuromodulation of distant circuits associated with stress, learning and affiliative behaviors (Landgraf, 2005). Interference with VP or PACAP signaling can alter anxiety-related behavior (Landgraf et al. 1995; Hashimoto et al, 2001). Using an elevated plus maze we observed an increased open arm time for PACAP KO vs WT: 81.4+14.3 vs. 47.5+10.9 sec, respectively (p<0.07, n=16) while time spent in closed arm was similar, indicating reduced anxiety as a result of PACAP gene deletion. 

Results:  Next, we subjected PACAP KO mice to an olfactory-driven social discrimination task which used gonadally intact females presented within corrals inside clean test cages (MacBeth et al, 2009). Compared to WT mice, PACAP KO male mice were unable to discriminate a novel from a familiar female since time spent investigating novel or familiar females was not different: 47.3+2.9 and 45.9+5.7 sec, respectively (p=0.83, n= 8). Total investigation time in all trials remained constant. Olfactory testing using non-social stimuli indicated no deficits between PACAP KO and WT in distinguishing olfactory-based preference to stimuli. 

Conclusions:  

Recently, we have shown that PACAP-deficient mice show aberrant VP and nitric oxide (NO) release from magnocellular neuroendocrine cells (MNCs) in supraoptic tissue punches challenged with acute hyperosmolarity  (Shahidizadeh et al, 2009). In this study we show that PACAP deficiency leads to more dramatic suppression of osmotic-activated vasopressin responses. Further, we show that PACAP gene deletion is associated with impairments in social discrimination behavior and anxiety responses. Our findings suggest that PACAP-operated circuits are critical for anxiogenic and social discriminative behaviors and that PACAP deficiency may be associated with and autistic-like phenotype.  Supported by MARC (M.V.), UCLeads (C.B.) and Department of Education funds (A.K., R.N.).