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Previously, we have shown significant associations between maternal hypertension (HTN) and Autism spectrum disorders (ASD) features, mainly as a social deficit in male offspring. Tuberous sclerosis complex (TSC2) is an autosomal dominant disease with rates of autism reaching 50%. We aim to characterize a novel double knockout mouse model that examines TSC2 and maternal HTN as genetic and environmental risk factors, respectively, for ASD phenotype in the offspring.
We bred male heterozygous TSC2 knockout mice (TSC2+⁄−) to HTN females that are heterozygous knockouts for endothelial nitric oxide synthase (eNOS+⁄−), as well as normotensives females (eNOS+⁄+) to generate hemizygous knockout offspring with and without genetic (TSC2+⁄−) and environmental (eNOS+⁄−) risk factors (Figure 1).
TSC2+⁄− and TSC2+⁄+ offspring born to a HTN mother (abnormal uterine environment), were compared to each other and to those born to normotensive mothers (normal uterine environment). Using validated behavioral tasks, we blindly tested for ASD-like features (Figure 2). Adjustments for gender were also performed.
Offspring with and without genetic and environmental risk factors performed similarly in behavioral tasks assessing motor function (Beam Balance, P=0.196; RotaRod, P=0.284), spatial learning and memory (Morris water maze, P=0.206), and anxiety (marble burying, P=0.374; Light/Dark Box, P=0.568).
In contrast, there was a significant interaction between the genetic and environmental risk factors in a social behavior task in which the time spent interacting with an object versus another animal was measured (Sociability task, genotype P=0.056, environment P=0.203, interaction of genetic risk with environmental factor P=0.048).
After adjusting for gender, there was a social deficit in males as compared to females, and that deficit was driven by the HTN environmental factor and not the TSC2 genetic risk (Sociability task, male gender P=0.014, eNOS+⁄- P=0.013, and TSC2+⁄− P=0.135). Interaction of male gender and environmental factor was also significant (P=0.009).
This novel double hemizygous knockout model supports a 2 hit hypothesis, where genetic factors and maternal HTN environmental exposure both contribute to ASD-like behavior, that is exhibited predominantly in males.