Abstract
BackgroundAutism spectrum disorder (ASD) is a heritable, heterogeneous neurodevelopmental disorder that is four times more likely to affect males than females. Despite this overt sex bias, it is unclear how genetic mutations associated with ASD alter cortical circuitry to produce the behavioral phenotypes by which ASD is diagnosed. Contactin-associated protein-like 2 (CNTNAP2) is an ASD-associated gene, and while Cntnap2 knockout (KO) mice recapitulate many of the features of ASD, the effect on cortical circuitry is poorly understood. Moreover, although heterozygous (Het) mice are the more relevant genotype for ASD-linked CNTNAP2 mutations in humans, to our knowledge, no effects in Het mice have been previously reported.MethodsIntrinsic signal optical imaging was used to measure functional visual responses in primary and higher visual cortical areas in male and female Cntnap2 KO, Het, and wild-type (WT) mice. Main effect of genotype was assessed with one-way ANOVA. Visual responses were also measured in P17–18 and P30–32 KO and WT mice. Main effects of age and genotype were assessed using two-way ANOVA.ResultsVisually evoked activity in dorsal stream associated higher visual areas in both KO and Het adult males was decreased relative to WT adult males. This decrease was not observed in adult females. Additionally, no significant difference was observed between WT and KO males at P17–18 with differences beginning to emerge at P30–32.ConclusionsThe functional responses of cortical circuitry in male mice are more strongly affected by Cntnap2 mutations than females, an effect present even in Hets. The observed differences in males emerge with development beginning at P30–32. These results reveal genotype- and sex-dependent effects of altered Cntnap2 expression and can shed light on the sex-dependent incidence of ASD.
Highlights
Autism spectrum disorder (ASD) is a heritable, heterogeneous neurodevelopmental disorder that is four times more likely to affect males than females
We found that differences in Cntnap2 expression levels had no effect on activity in lateromedial area (LM) in either males or females (Males LM: one-way ANOVA F(2,18) = 1.96, p = 0.17; Females LM: one-way ANOVA, F(2,18) = 0.248, p = 0.78; n = 21 measurements per Higher visual area (HVA), 21 animals, 7 per genotype) (Fig. 2c, d)
Genotype-dependent and sex-dependent decreases in dorsal HVAs we examined the effects of changes in Cntnap2 expression levels on dorsal steam-associated areas Anterolateral area (AL), rostrolateral area (RL), and Anteromedial area (AM)/posteromedial area (PM) in both males and females
Summary
Autism spectrum disorder (ASD) is a heritable, heterogeneous neurodevelopmental disorder that is four times more likely to affect males than females. Despite this overt sex bias, it is unclear how genetic mutations associated with ASD alter cortical circuitry to produce the behavioral phenotypes by which ASD is diagnosed. Individuals with autism spectrum disorder (ASD) have characteristic impairments in social interaction and communication, and restricted, repetitive behaviors and interests that emerge around 2–3 years of age [1]. Mouse models lacking Cntnap recapitulate the hallmark features of ASD, including repetitive behaviors and impairments in social interaction and communication [15, 16]. The effects of this gene on the functional development of the brain remain unclear
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