642. Lithium mitigates autism-like behaviors and neuroinflammation in a valproic acid-induced rat model of autism spectrum disorder

Abstract

Abstract Background Autism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by social interaction deficits, communication challenges, and repetitive behaviors. The prevalence of ASD has increased significantly. Despite the growing recognition of ASD, effective pharmacological treatments for core symptoms are lacking. Lithium, a neuroprotective agent known for its effects in psychiatric disorders, has shown promise in treating neurological damage but remains underexplored in the context of ASD. Aims & Objectives This study investigates the neuroprotective effects of lithium in the valproic acid (VPA)-induced rat model of autism. We aim to evaluate lithium’s impact on behavioral abnormalities, neuronal morphology, and neuroinflammatory responses in the medial prefrontal cortex (mPFC) and hypothesize that lithium will alleviate ASD-like symptoms and restore synaptic function. Method We used the VPA-induced rat model, where valproic acid was administered to pregnant Wistar rats on embryonic day 12.5. Lithium chloride (1 mmol/kg) was administered daily to the offspring from postnatal days 5 to 32. Behavioral tests including grooming, marble-burying, open-field, and three-chamber tests assessed ASD-like behaviors. Upon sacrifice at postnatal day 44, morphological analyses (Golgi staining, immunofluorescence for microglia and astrocytes) and electrophysiological recordings were performed to evaluate neuronal structure and synaptic function in the mPFC. Results Lithium treatment significantly improved the behavioral deficits of VPA rats. Specifically, lithium reduced grooming and marble-burying behaviors, indicating a decrease in repetitive actions. The open-field test revealed reduced anxiety, and the three-chamber test showed increased social interaction and preference for a novel conspecific, suggesting improved social behavior. Lithium treatment also enhanced dendritic length, branching, and spine density in both male and female rats, with more pronounced effects in males. Immunofluorescence analysis revealed reduced microglial activation and preserved NeuN-positive neurons, particularly in male rats. Electrophysiological recordings indicated that lithium improved action potential firing, as well as glutamatergic and GABAergic transmission in mPFC neurons. Discussion & Conclusions These results suggest that lithium has significant neuroprotective effects in the VPA-induced rat model of autism. Lithium treatment improved behavioral outcomes, restored dendritic structure, and enhanced synaptic transmission. It also reduced neuroinflammation, further supporting its potential as a therapeutic intervention for ASD. Additionally, our findings highlight sex-specific differences in the response to prenatal VPA exposure, with male rats showing more profound changes. Overall, lithium represents a promising candidate for clinical trials targeting core ASD symptoms.