Hyperactivity and male‐specific sleep deficits in the 16p11.2 deletion mouse model of autism

Abstract

Sleep disturbances and hyperactivity are prevalent in several neurodevelopmental disorders, including autism spectrum disorders (ASDs) and attention deficit-hyperactivity disorder (ADHD). Evidence from genome-wide association studies indicates that chromosomal copy number variations (CNVs) are associated with increased prevalence of these neurodevelopmental disorders. In particular, CNVs in chromosomal region 16p11.2 profoundly increase the risk for ASD and ADHD, disorders that are more common in males than females. We hypothesized that mice hemizygous for the 16p11.2 deletion (16p11.2 del/+) would exhibit sex-specific sleep and activity alterations. To test this hypothesis, we recorded activity patterns using infrared beam breaks in the home-cage of adult male and female 16p11.2 del/+ and wildtype (WT) littermates. In comparison to controls, we found that both male and female 16p11.2 del/+ mice exhibited robust home-cage hyperactivity. In additional experiments, sleep was assessed by polysomnography over a 24-hr period. 16p11.2 del/+ male, but not female mice, exhibited significantly more time awake and significantly less time in non-rapid-eye-movement (NREM) sleep during the 24-hr period than wildtype littermates. Analysis of bouts of sleep and wakefulness revealed that 16p11.2 del/+ males, but not females, spent a significantly greater proportion of wake time in long bouts of consolidated wakefulness (greater than 42 min in duration) compared to controls. These changes in hyperactivity, wake time, and wake time distribution in the males resemble sleep disturbances observed in human ASD and ADHD patients, suggesting that the 16p11.2 del/+ mouse model may be a useful genetic model for studying sleep and activity problems in human neurodevelopmental disorders.

Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders

“…(* = p < 0.05, *** = p < 0.001) neurodevelopmental disorders. In our experiments, we find differences in many phenotypes, including developmental milestones, motor activity, anxiety-like behavior, and cognition [Angelakos et al, 2017;Grissom et al, 2017;Horev et al, 2011;V. Kumar et al, 2018;Nickl-Jockschat et al, 2015;Portmann et al, 2014;Yang, Mahrt, Lewis, et al, 2015].…”

The autism-associated gene Scn2a plays an essential role in synaptic stability and learning

“…Whether female Scn2a +/- are similarly resistant to spatial learning impairments has not been explored. Nevertheless, these data add to a growing body of literature highlighting sex-based differences in the behavior of neurodevelopmental disorder models (Angelakos et al, 2017; Dhamne et al, 2017; Grissom et al, 2018; Reith et al, 2013; Schmeisser et al, 2012; Zamarbide et al, 2018), paralleling the sex biases observed in ASD and, to a lesser extent, ID (Fischbach and Lord, 2010; Kim et al, 2011). While we provide insight into how cortical physiology is altered by Scn2a loss, future work will be needed to elucidate the cellular and synaptic consequences of Scn2a haploinsufficiency in regions outside of PFC, and whether region-specific impairments underlie behavioral deficits in a sex-specific manner.…”

Sex Differences in Autism Spectrum Disorder: a Review

“…Other recent reports using mouse models of ASD indicate that two hits--male sex and particular genetic mutations--may be sufficient to result in autism-relevant phenotypes. Findings include sleep disturbances in 16p11.2 del/+ male mice, social and morphological deficits in male Pcdh10 +/− mice, and increased social motivation in male Pten mutant mice [45,222,223]. Purkinje cell abnormalities were male-specific in the Reeler mouse model of ASD, and the Adnp mouse model of ASD shows sex-specific hippocampal gene expression, behavior alterations, and response to treatment [224,225].…”