Targeting Brain Plasticity: Vagal Nerve Stimulation as a Therapy for Autism‐Like Symptoms in a Valproic Acid Mouse Model

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition defined by social deficits, stereotypical or repetitive behaviors, and anxiety. This study evaluates the therapeutic potential of transauricular vagal nerve stimulation (tVNS) in a valproic acid (VPA)-induced mouse model of ASD. The study comprised three groups: the control + sham (saline-treated offsprings receiving sham stimulation), the autistic + sham (VPA-treated offspring receiving sham stimulation), and the autistic + tVNS (VPA-treated offsprings receiving tVNS). Male C57BL/6 mice exposed to VPA on embryonic day 12.5 were evaluated for behavioral and neurobiological alterations. tVNS was applied twice weekly for 3 weeks to investigate its effects on sociability, anxiety-like behaviors, neurogenesis markers, and apoptosis pathways. Behavioral testing, including the three-chamber test, mirrored chamber test, open field test, and elevated plus maze, revealed that tVNS significantly improved sociability and social preference indices, reduced social anxiety, and decreased general anxiety-like behaviors in VPA-induced mice. Histological and immunohistochemical analyses have shown a decrease in neuron density, brain-derived neurotrophic factor (BDNF), and doublecortin (DCX) expression in the hippocampus, amygdala, and prefrontal cortex of VPA-induced mice. Additionally, the increase in caspase-3 immunoreactivity indicates increased apoptosis. tVNS treatment restored BDNF and DCX levels, promoting neurogenesis and synaptic plasticity while significantly reducing caspase-3-mediated apoptosis in affected brain regions. These findings suggest that tVNS may counteract the neural and behavioral deficits associated with ASD by modulating neurogenesis, neuronal plasticity, and apoptosis. The study highlights tVNS as a potential therapeutic intervention for ASD, emphasizing its role in targeting both behavioral alterations and underlying neurobiological mechanisms.