Preserved autism-associated behaviors and dopaminergic neuron hyperactivity in DAT-IRES-Cre mice after valproate exposure.

Abstract

Dopamine (DA) signaling is implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD). Cell-type-specific tools like DAT-IRES-Cre mice are essential for dissecting the underlying circuit mechanisms. However, as the transgenic Cre insertion may affect DA transmission, it is crucial to validate that these Cre mice recapitulate key physiological and behavioral phenotypes in established ASD models. Prenatal exposure to valproic acid (VPA) is a widely used ASD model that captures gene-environment interactions in etiology, and DA system dysfunction has been reported in this model including our studies. Here, we evaluated the suitability of the DAT-IRES-Cre strain in this VPA-induced ASD model. We systematically assessed neurodevelopmental milestones, autism-associated behaviors including repetitive and social behaviors, tyrosine hydroxylase (TH) expression, and the electrophysiological properties of DA neurons. Following prenatal VPA exposure, DAT-IRES-Cre offspring exhibited comparable neurodevelopmental delays and autism-associated behavioral deficits as those in wild-type mice. Both strains also exhibited upregulated TH expression after VPA exposure. Electrophysiological recordings further revealed similar hyperactivity of DA neurons, characterized by enhanced excitatory synaptic drive and excitability in VPA-exposed DAT-IRES-Cre and C57BL/6J wild-type offspring. Moreover, under baseline conditions, there were no significant differences were detected between saline-treated DAT-IRES-Cre and wild-type mice. In conclusion, the DAT-IRES-Cre mice could serve as a reliable tool for implementing cell-type-specific strategies to investigate DA circuit mechanisms in the VPA model of ASD.