Rationale: Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric or behavioral consequences of AEDs present as: (i) reversible changes in mood, anxiety and/or irritability that often necessitate discontinuation, and (ii) pervasive cognitive and psychomotor alterations secondary to fetal exposure. Technical advances in visualizing and quantifying higher order patterns of naturalistic rodent behaviors may provide for more sensitive preclinical assessments of AED tolerability and cognitive teratogenicity. Methods: Using instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice (of both sexes), and in the adult offspring of VPA-exposed breeder pairs. Using a pup open field assay, we also clarified how prenatal VPA exposure impacts early spontaneous exploratory behavior. Results: At 500-600 mg/kg/d, chronic VPA exposure (four weeks) produced hyperphagia and increased wheel-running without impacting sleep, activity or home-cage measures of risk aversion. When applied to breeder pairs of mice, VPA at this dose prolonged the latency to viable litters without affecting litter size. At two weeks of age, VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, together with hypophagia, increased wheel running and subtle alterations in dyadic behavior. Conclusions: Through automated home-cage assessments of mouse behavior, we capture an ethologically sound psychopharmacological profile of enteral VPA that is well-aligned with human clinical experience. By examining mice exposed prenatally to similar doses of VPA, this approach reveals murine manifestations of pervasive neurodevelopment in an enormously popular autism model. Incorporating rigorously validated preclinical assessments of neuropsychiatric tolerability may inform the design and selection of future AEDs (and other neurotherapeutics) with improved psychiatric safety profiles, both for patients and their offspring.
Funding: Please list any funding that was received in support of this abstract.: VK receives support from the NIH (1K08NS110924-01), an AES Junior Investigator Award (2020), SK Life Science, and seed funding from Baylor College of Medicine’s Office of Research.
