NMDA Receptor and Associated Intracellular Proteins in Amygdala and Hippocampus in Depression

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Accumulating evidence suggests dysfunction of the glutamate signaling system in major depressive disorder. Previously, we observed elevated levels of NR2C subunit of N-methyl-D-aspartate receptor (NMDAR) and lower levels of neuronal nitric oxide synthase (nNOS), intracellular mediator of NMDAR activation, in the noradrenergic locus coeruleus in depressed subjects (Karolewicz et al. 2004, 2005). The aim of the present study was to investigate potential abnormalities in the NMDAR signaling molecules in the amygdala and hippocampus from the same depressed subjects. Tissue samples containing the lateral nucleus of amygdala, and hippocampal dentate gyrus were obtained from 10 -11 matched pairs of depressed subjects and healthy controls. Subjects were matched for age, sex, brain pH, and postmortem interval. Changes in concentration of NMDAR subunits NR1 and NR2 as well as intracellular associated proteins, neuronal nitric oxide synthase (nNOS) and postsynaptic density protein (PSD-95), that might occur in depression were assessed by immunoblotting. NR1 subunit immunoreactivity appeared as a prominent band at 120 kDa; NR2A as a band at 180 kDa; PSD-95 and nNOS immunoreactivities appeared as bands at 95 kDa and 155 kDa, respectively. The overall amount of NR1 and nNOS was normal in subjects diagnosed with depression as compared to controls. Amounts of PSD-95 were significantly higher in the amygdala (+115%, p<0.05) and hippocampus (+34%, p<0.05), respectively. The level of NR2A subunit was elevated in the amygdala (+51%) in depressed subjects as compared to controls. Our data indicate that glutamatergic signaling is abnormal in depression. Higher levels of NMDA receptor subunits and its associated protein may represent an adaptive response to decreased synaptic release of glutamate. This hypothesis is in agreement with postmortem and neuroimaging findings of altered glutamatergic transmission in depression. Further studies of the glutamatergic signaling system may lead to the development of novel therapeutics for the treatment of depressive disorder.

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