(915.4) Anti-Epileptic Drug and Teratogen Valproic Acid Induces  Microglial Cell Death in a Valproic Acid Murine Model of Autism

Poster Board Number: B197

Allison Loyola (Idaho State University College of Pharmacy), Alok Bhushan (Thomas Jefferson University), Prabha Awale (Idaho State University College of Pharmacy)

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects approximately 1 in 44 children in North America, and its association with neuronal connectivity is an area of intense research. Valproic acid (VPA) is a multi-target drug widely used to treat epilepsy. It is classified as a teratogen and as a histone deacetylase inhibitor (HDACi) and fetal exposure to VPA increases the risk of ASD.The VPA model has been well characterized for behavioral and neuronal deficits, including hyperconnectivity. The cause of  hyperconnectivity is poorly understood however, it is speculated that lack of pruning may be partly responsible for this anomaly. Microglia, the principal immune cells of CNS regulate dendrite and synapse formation during early brain development. The effect of VPA on microglia during early development has not been well characterized and may provide potential hints regarding the etiology of this disorder. Preliminary studies from our lab indicate that VPA reduces microglial number during peak periods of postnatal synaptogenesis in the mouse brain primary cortex. Nevertheless, the cause of this reduction is not known. Therefore, in this study, we determined the mechanism for reduced microglial numbers in the VPA model of autism.Pregnant BALBc mice were administered 600 mg/kg of VPA by subcutaneous injection on day 13.5 of gestation. We harvested the mice brains at embryonic (E) day 14, E17, and postnatal day 1 (PD1). Brain tissue was double immunolabeled for microglia (IBA1) and cell death marker (TUNEL). We found a gradual increase in TUNEL staining beginning E14 to PD1 compared to age-matched controls. The mechanism for reduced microglial number may be due to cell death. Thus, our findings possibly have pathophysiological/pathogenic implications in autism and may, ultimately, lead to the discovery of new therapeutic target(s) for autism.