Cognitive Impairments in a Mouse Model of 16p11.2 Deletion Syndrome

Background:  15% of patients with a ~600kb deletion in the human chromosomal region 16p11.2 have autism (Marshall et al., 2008; Weiss et al., 2008; Zufferey et al., 2012). 16p11.2 deletions and duplications are also associated with speech delay, intellectual impairment, and developmental delays (Hanson et al., 2010; Owen et al., 2014). Two mouse models of 16p11.2 deletion syndrome were independently generated (Horev et al. 2011; Portmann et al. 2014), in which the syntenic region on mouse chromosome 7F3 was heterozygously deleted. Both models exhibited low body weight, perinatal mortality, and sporadic motor stereotypies. We previously reported that juvenile and adult 16p11.2 +/- males and females exhibited normal general health, neurological reflexes, responses to social and non-social odors, motor learning, normal social approach, normal juvenile reciprocal social interaction, and a novel object recognition deficit (Portmann et al. 2014). 

Objectives:  The present study was designed to replicate the initial finding of novel object recognition deficits, and evaluate the generalization of cognitive deficits in 16p11.2 mice as compared to wildtype littermates across a range of assays:  a) preference for social novelty as a corroborative measure of novel recognition, b) acquisition and reversal learning of a pairwise visual discrimination task using the  Bussey–Saksida operant touchscreen equipment as a measure of cortical dependent recognition learning and memory, and c) contextual fear conditioning as a measure of hippocampal-depending emotional learning and memory. 

Methods:  Novel object recognition measured seconds spent sniffing two identical objects, then 1 hour later, time spent sniffing one now-familiar object and a new object (coral or treasure chest plastic toys).  Standardized Med Associates automated equipment calculated time spent freezing during the fear conditioning session 1 day after the aversive association training session. Touchscreen pairwise visual discrimination and reversal were modified from Silverman et al., 2013. Mice were trained to discriminate two illumination-matched images on the touch-sensitive panel of an operant chamber. Touching the correct image triggered a 2-s flashing light that signaled the mouse to retrieve 50µl of strawberry flavored Ensure reinforcer. Days to reach criterion during the initial learning, and days to criterion on reversal learning, were compared between genotypes using Student t-test.  

Results:  Robust novel object recognition deficits were replicated in two new cohorts of 16p11.2 +/- mice. 16p11.2 +/- mice did not exhibit preference for social novelty when presented with a familiar versus an unfamiliar 129Sv/ImJ mouse, indicating deficits in social recognition. Contextual conditioning was normal in two cohorts of +/- mice. In the touchscreen test, 16p11.2 +/- required significantly more days than +/+ to reach criteria during both the acquisition and reversal phases, indicating learning deficits and cognitive inflexibility.    

Conclusions:  16p11.2 deletion caused robust deficits in tasks that require discriminating differences between familiar versus novel objects or conspecifics, and on pairwise visual discrimination and reversal learning. These phenotypes support the use of 16p11.2 deletion mice as a model for aspects of intellectual disabilities in 16p11.2 deletion patients with autism.