Developmental Trajectory of Autistic‐Like Behaviors in a Prenatal Valproic Acid Rat Model of Autism

ABSTRACT Autism spectrum disorders (ASDs) are characterized by deficits in social functioning, stereotyped patterns of behaviors, narrowed interests, and elevated anxiety. Certain ASD symptoms can persist, whereas others may improve throughout the lifespan, but the specific patterns of changes have not been clearly delineated. Using a valproic acid (VPA) rat model of ASD, the present study took a developmental approach and examined how autistic‐like behaviors, including anxiety‐like behavior, object obsession, and social functioning deficits, manifested differently in three critical periods representing preadolescent (postnatal day [PND] 25), adolescent (PND 45), and adulthood life stage (PND 75) in a sex‐dependent manner. Starting on PNDs 25, 45, and 75, VPA‐ or saline‐exposed male and female offspring were tested in an elevated plus maze (EPM) and a newly validated composite social and object interaction and a triple recognition test (object, spatial, and social recognition). Across the three age groups, VPA‐exposed offspring did not exhibit enhanced anxiety‐like behavior in the EPM nor enhanced object interaction (“object obsession”) in the triple recognition test. However, both male and female preadolescent (PND 25) VPA‐exposed offspring showed a significantly increased latency to initiate social contact than the saline‐exposed controls, although their latencies to contact novel objects were comparable to those of the controls. Male preadolescent and adolescent VPA‐exposed offspring, to a lesser extent the female preadolescent offspring, exhibited significantly lower levels of social interaction. These social functioning deficits were absent in adult VPA offspring. Additionally, prenatal VPA exposure did not cause an impairment of object recognition, spatial recognition, or social recognition of a familiar conspecific. Unexpectedly, it enhanced social recognition of a novel conspecific, but only in adolescent female offspring. These findings suggest that this rat model based on prenatal VPA exposure is valid in capturing early social motivational and functioning deficits but is limited in its capacity to model increased object obsession and enhanced anxiety as seen in ASD, as well as the developmental trajectory of non‐social ASD symptoms. Recognizing these limitations is important as it informs us how to properly use this model to investigate the neurobiology of ASD and incentivizes us to develop better rodent models.