Prenatal methotrexate injection increases behaviors possibly associated with depression and/or autism in rat offspring; A new animal model for mental disorder, based on folate metabolism deficit during pregnancy

BACKGROUND: Deficiency of folate, an essential vitamin for DNA synthesis and methylation, is reported as a risk factor for mental disorders. Considering a possibility that folate metabolism deficit during pregnancy may disturb CNS development and increase mental disorders in offspring, we treated pregnant rats with methotrexate (MTX), an inhibitor of folate metabolic enzyme, and evaluated offspring behaviors. METHODS: Saline or MTX was intraperitoneally administered to female SD rats on gestational day 17. Offspring behaviors were evaluated during approximately 6–9 weeks old; prepulse inhibition (PPI), social interaction (SI), locomotor activity (LA), and forced swimming test (FST) for evaluation of schizophrenia, depression, and autism related behaviors; the elevated plus maze (EPM) and the light–dark box (LD) test for evaluation of anxiety. RESULTS: Compared to saline‐treated group, MTX‐treated group showed decrease of SI and increase of immobility time in FST. In addition, increases of time spent in the light box and shuttling between the light–dark boxes were observed in LD test. On the other hand, no changes were confirmed in EPM, LA, and PPI. CONCLUSION: Decrease of SI and increase of immobility time in FST may suggest association of this animal model with depression and/or autism. Increase of time spent in the light box and shuttling between the light–dark boxes may indicate changes in anxiety or cognitive level to environment, or repetitive behaviors in autism. Although further studies are warranted to characterize this animal model, at least we can say that prenatal MTX exposure, possibly causing folate metabolism deficit, affects offspring behaviors.