Prenatal Exposure To Valproic Acid Induces Increased Autism-Like Behaviors and Impairment of Learning and Memory Functions in Rat Offspring by Upregulating ADAM10 Expression

Abstract

Autism spectrum disorder (ASD) involves a complex neurodevelopmental pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) plays a crucial role in embryonic brain development and neural network stability. This study aimed to investigate the influence of ADAM10 on excitation/inhibition (E/I) balance, autism-like behaviors, and learning and memory dysfunction in rats prenatally exposed to valproic acid (VPA) and determine potential intervention strategies. The VPA-exposed group exhibited increased levels of ADAM10 and secreted amyloid precursor protein-α (sAPPα). Moreover, overexpression of glutamate decarboxylase 1 and N-methyl-D-aspartate receptors was observed. High-performance liquid chromatography-mass spectrometry revealed elevated levels of glutamate, glutamine, and γ-aminobutyric acid, as well as an E/I imbalance in the VPA group. Additionally, narrower synaptic clefts as well as increased postsynaptic density and synaptic vesicles were observed. Remarkably, intraperitoneal administration of ADAM10 inhibitor during the critical period of synaptic development significantly improved ASD-like behavior and learning and memory function in VPA-exposed rats. This intervention effectively reduced abnormally high sAPPα levels in the prefrontal cortex and corrected abnormal E/I balance. Thus, inhibiting ADAM10 overexpression may improve the E/I imbalance, alleviate core symptoms of ASD, and improve learning and memory dysfunction. The use of ADAM10 inhibitor represents a potential therapeutic strategy for treating ASD patients with intellectual disabilities.