Premium
Exposure to Homocysteic Acid Early in Postnatal Development Leads to a Mixed Depressive/Manic Behavioral Phenotype and Changes in NMDA Receptor Expression
Author(s) -
Simko Stephanie,
Johnson Jacob,
Flores Guillermo,
Barney Christopher C.,
Chase Leah
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1076.3
Subject(s) - endocrinology , medicine , hippocampus , anhedonia , nmda receptor , psychology , receptor , dopamine
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 behaviors associated with MDD and/or bipolar disorder. Twenty postnatal male and twenty female rats were injected daily with either HCA or saline from day P3 to P21. HCA‐treated rats displayed increased risk‐taking behavior, reduced social behavior, novelty‐induced hyper‐locomotion, anhedonia in the saccharine preference test, and reduced spatial learning in the Morris water maze, consistent with a depressive state with manic tendencies. Interestingly, female rats were more sensitive to the effects of HCA than male rats. As expected, HCA treatment had no effect on motor coordination (Rotarod) or startle behavior (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. We also observed a significant change in the NMDAR2b:NMDAR2a subunit expression ratio in the cortex. Specifically, HCA triggers an increase in the NMDAR2b:NMDAR2a ratio in male rats, while female rats exhibit a decrease in this ratio. We also observed that HCA triggered an increase in NMDAR2a expression in the hippocampus in both males and females. Finally, HCA also led to a decrease in NMDAR2b expression in females, but an increase in NMDAR2b expression males in the hippocampus. 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 also be accompanied by changes in GABAergic signaling in the cortex. Given the role that NMDA receptors are proposed to play in regulating GABAergic interneuron activity and the regulation of mood, we suggest that this may serve as a novel animal model for studies of complex mood disorders such as bipolar disorder or major depressive disorder. Support or Funding Information This research was supported by the Hope College Neuroscience Program, Biology Department and Chemistry Department.