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.

Researchers gave pregnant rats a drug that blocks folate (a B vitamin) to see if this affected their babies' behavior. The baby rats showed less social behavior and more signs of giving up easily - behaviors that might be similar to depression or autism in humans. They also showed some unusual responses to light and dark environments. This suggests that not getting enough folate during pregnancy might affect brain development and behavior in offspring.

This preclinical study investigated whether folate deficiency during pregnancy affects offspring behavior by administering methotrexate (MTX) to pregnant rats on gestational day 17. Offspring were assessed at 6-9 weeks old using multiple behavioral tests. MTX-exposed offspring showed decreased social interaction and increased immobility in forced swimming tests, behaviors potentially associated with depression and/or autism. Additionally, they spent more time in light environments and showed increased shuttling behavior, which may indicate altered anxiety responses or repetitive behaviors.

No changes were observed in prepulse inhibition, locomotor activity, or elevated plus maze tests. The researchers propose this as a potential animal model for studying mental disorders related to prenatal folate metabolism deficits.

Provides preliminary evidence that prenatal folate metabolism disruption may affect offspring neurodevelopment and behavior. May support importance of adequate folate during pregnancy, though human studies needed to establish clinical relevance for autism or depression prevention.

Single study using animal model with small behavioral battery. Human relevance uncertain. Sample size not reported. Limited characterization of the proposed model. Single timepoint of MTX administration. Behavioral assessments focused on limited age range.

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. 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.

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. 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.