Prenatal GABAB Receptor Agonist Administration Corrects the Inheritance of Autism-Like Core Behaviors in Offspring of Mice Prenatally Exposed to Valproic Acid

Abstract

This study was performed to evaluate the effects of prenatal baclofen (a GABAB receptor agonist) treatment on the inheritance of autism-like behaviors in valproic acid (VPA)-exposed mice. VPA model mice (first generation, F1) that were prenatally exposed to VPA exhibited robust core autism-like behaviors, and we found that oral administration of baclofen to F1 mice corrected their autism-like behavioral phenotypes at an early age. Based on a previous epigenetics study, we mated the F1 male offspring with litter females to produce the second generation (F2). The F2 male mice showed obvious inheritance of autism-like phenotypes from F1 mice, implying the heritability of autism symptoms in patients with prenatal VPA exposure. Furthermore, we found prenatal baclofen administration was associated with beneficial effects on the autism-like phenotype in F2 male mice. This may have involved corrections in the density of total/mature dendritic spines in the hippocampus (HC) and medial prefrontal cortex (mPFC), normalizing synaptic plasticity. In this research, GABAB receptor agonist administration corrected the core autism-like behaviors of F1 mice and protected against the inheritance of neurodevelopmental disorders in the offspring of F1 mice, suggesting the potential of early intervention with GABAB receptor agonists in the treatment of neurodevelopmental disorders.