Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPAE12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPAE12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPAE12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPAE12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPAE12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder. © FASEB.