Exposure to Homocysteic Acid Early in Postnatal Development Leads to a Mixed Depressive/Manic Behavioral Phenotype and Changes in NMDA Receptor Expression
Dr. Leah A. Chase, Neuroscience Program and Departments of Biology and Chemistry, Dr. Christopher C. Barney, Biology Department
Homocysteic acid (HCA), a NMDA receptor agonist, is an endogenous metabolite formed from the oxidation of homocysteine. Since hyperhomocysteinemia is a risk factor for several neuropsychiatric disorders, including bipolar disorder and major depressive disorder (MDD), we tested the hypothesis that elevated HCA levels in developing rats may induce alterations in NMDA receptor expression and the development of associated behaviors. Twenty postnatal male and twenty female rats were injected daily with either HCA or saline from P3 to P21. HCA-treated rats displayed increased risk-taking behavior, reduced social behavior, novelty-induced hyper-locomotion, anhedonia, and reduced spatial learning, consistent with a depressive state with manic tendencies. As expected, HCA treatment had no effect on motor coordination or paired-pulse inhibition. In addition to these behavioral changes, we observed that HCA led to an increase in expression of the GABAergic marker, GAD-67, in the cortex, but not the hippocampus, of both male and female rats. In the cortex, we also observed that HCA triggers a significant increase in the NMDAR2b:NMDAR2a subunit expression ratio in male rats, while female rats exhibited a decreased ratio. The results suggest that HCA triggered an increase in NMDAR2a expression in the hippocampus of both males and females. Finally, HCA also led to a decrease in NMDAR2b expression in females, but an increase in NMDAR2b expression in the hippocampus of males. We are currently examining the effect of HCA exposure on NMDAR1 subunit expression. Collectively, these data suggest that early postnatal exposure to HCA may lead to a mixed manic/depressive phenotype that may be accompanied by GABAergic signaling changes in the cortex. Given the proposed regulatory role of NMDA receptors on GABAergic interneuron activity and mood, we suggest that this may serve as a novel animal model for studies of complex mood disorders, such as bipolar disorder or MDD.
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