¹Division of Pharmaceutical Science, Faculty of Pharmacy, Meijo University, Nagoya, Japan, ²Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Science, Aichi, Japan, ³Division of Neurochemistry, International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan

Background: Autism spectrum disorders (ASD) are pervasive developmental disorders characterized by social deficits and restrictive patterns of behavior and interests. Epilepsy is comorbidity in ASD patients. The imbalance of neural excitation and inhibition is hypothesized for the pathophysiology of ASD as well as epilepsy. Lacosamide and perampanel are the new third-generation anti-seizure medications used for focal epilepsy. But it remains unclear whether these antiepileptic drugs that correct the balance between neural excitation and inhibition improve ASD symptoms.

Aims & Objectives: It is epidemiologically reported that administration of valproic acid (VPA) during pregnancy increases the risk of ASD in the offspring. In this study, we investigated therapeutic potential of lacosamide and perampanel for ASD in mice exposed to prenatal VPA.

Method: Pregnant mice were injected with VPA (500 mg/kg, i.p.) on gestational day 12. The offspring were subjected to social interaction test, novel object recognition test and repetitive behavior test. Lacosamide (1-15 mg/kg, i.p.) and perampanel (0.1-1.5 mg/kg, i.p.) were treated before each behavioral test. The mRNA expression levels of SCN2A, SCN4B and Arc in the prefrontal cortex were measured by real-time PCR.

Results: The mice exposed to prenatal VPA showed decrease in social interaction time and exploratory preference for novel object and increase in numbers grooming associated with increase of SCN2A, SCN4B and Arc mRNA levels in the prefrontal cortex. The lacosamide (1mg/kg), and perampanel (0.1mg/kg) attenuated these behavioral changes and decreased Arc mRNA expression levels in mice exposed to prenatal VPA.

Discussion & Conclusions: Behavioral changes in mice exposed to prenatal VPA were resembled symptoms of ASD. Increased levels of SCN2A, SCN4B, and Arc suggested hyper-excitability in the prefrontal cortex of mice exposed to prenatal VPA. The attenuation effect of lacosamide and perampanel at low doses on the ASD-like behaviors and hyper-excitability suggested that these antiepileptic drugs have therapeutic potential for treating ASD symptoms.