Prenatal Stress Alters Transcription of NMDA-Type Glutamate Receptors in the Hippocampus

Abstract Prenatal stress damages the development of the cortico-hippocampal circuit in the brain and increases the risk for neurological disorders associated with deficits of social behavior, including schizophrenia. Accumulating evidence indicates that the NMDA-type glutamate receptor plays an important role in social cognition and stress-induced pathology in the hippocampus. In this study we have tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex and hippocampus of prenatally stressed mice. Prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily during gestational weeks 2 and 3. We treated the adult offspring with haloperidol (1mg/kg), clozapine (5mg/kg) or vehicle (saline) twice daily for 5 days, after which we measured social interaction behavior (SI) and locomotor activity. After euthanasia, we measured the transcription of NMDAR subunits in the hippocampus and frontal cortex. We observed that saline-treated prenatally stressed (PRS-Sal) mice had reduced social interaction (SI) behavior compared to controls (NS-Sal) (P<0.01). This deficit was recovered in PRS mice treated with clozapine (PRS-Clz) but not the haloperidol-treated PRS group (PRS-Hal). These changes were not due to suppressed locomotion as neither PRS nor antipsychotic treatment reduced locomotor activity. These effects of prenatal stress were associated with increased transcription of NMDAR subunits (GRIN genes) in the hippocampus but not the frontal cortex. We observed positive correlation between GRIN transcription and social behavior in the frontal cortex, and conversely, negative correlation between GRIN transcription and social behavior in the hippocampus. Studies indicate that transcription of NMDARs is activity dependent, therefore altering the transcription levels of different NMDAR subunits would have a significant impact on the excitatory transmission in the corticolimbic circuit. The results suggest a molecular pathway by which prenatal stress in mice leads to life-long deficits in social behavior. It’s worth noting that while these associations have been observed in mice, the direct translation to human prenatal stress and NMDA receptor alterations requires further investigation. Nevertheless, these findings contribute to our understanding of the impact of prenatal stress on pathology in the hippocampus and downstream effects on social behavior and may have implications for understanding neuropsychiatric disorders related to prenatal stress exposure.