Prenatal valproic acid exposure-induces the hyper-NMDA receptor signaling in prefrontal cortex and autism spectrum disorder-like behaviors through hypo-signaling of 5-HT_1A receptor in mice.

Abstract

Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of autism spectrum disorder (ASD) in the offspring. In the pathophysiological hypothesis of ASD, excitation/inhibition (E/I) imbalance is attracted. Dysfunction of serotonergic system is also suggested to be involved in ASD. In this study, we investigated glutamatergic-serotonergic neuronal interaction in the ASD-like behavior induced by prenatal VPA exposure in mice. Prenatal VPA exposure induced not only excessive repetitive self-grooming behavior, impairments of social behavior and object recognition memory, but also increased glutamatergic signaling (CaMKII phosphorylation) and decreased serotonin contents in the prefrontal cortex. Memantine (low-affinity NMDA antagonist) suppressed both the increase of CaMKII phosphorylation and ASD-like behaviors. Activation of serotonergic signaling via 5-HT_1A receptor by fluoxetine, tandospirone (5-HT_1A receptor agonist) and optogenetics attenuated the ASD-like behaviors in prenatal VPA-exposed mice. WAY-100635 (5-HT_1A receptor antagonist) antagonized the effect of fluoxetine on the ASD-like behaviors. These results suggest that the hyper-NMDA receptor signaling and ASD-like behaviors are associated with hypo-signaling of 5-HT_1A receptor in the prenatal VPA-exposed mice.