This section highlights a recent publication by one or more of the CPN researchers. It is updated periodically to reflect the cutting edge research taking place at the CPN.
Glutamate System in Depression
Beata Karolewicz, Ph.D., Principal Investigator
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KAROLEWICZ B, STOCKMEIER CA, ORDWAY GA. Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacology 2005;30:1557-1567. Pubmed link
KAROLEWICZ B, SZEBENI K, STOCKMEIER CA, KONICK L, OVERHOLSER JC, JURJUS G, ROTH BL, ORDWAY GA. Low nNOS protein in the locus coeruleus in major depression. J Neurochemistry 2004;91:1057-1066. Pubmed link
Background: Major depression is one of the most common psychiatric disorders and leading cause of disability worldwide. Only 60% of depressed patients can be successfully treated with conventional antidepressants which were developed based on the existing monoamine theory of depression. Therefore, there is a possibility that other neurotransmitter systems may also contribute to the pathophysiology of depression and the mechanism of antidepressant action.
Recent research provides compelling evidence for a dysfunction of the glutamate system in major depressive disorder and the involvement of glutamate N-methyl-D-aspartate receptors (NMDAR) in antidepressant activity . The functional NMDAR is a heterooligomeric structure composed of NR1 and NR2 (A-D) regulatory subunits. At synapses, NMDARs are stabilized through interactions with postsynaptic density proteins (PSD-95). PSD-95 is a critical component of the molecular mechanism responsible for the clustering of NMDARs at synapses. Moreover, PSD-95 provides structural and functional coupling of the NMDAR with neuronal nitric oxide synthase (nNOS), an intracellular mediator of NMDAR activation.
Advance: Our investigations using postmortem human brain tissue have provided the first evidence of the abnormal glutamatergic signaling in the brainstem from subjects diagnosed with depression. For example, a significant increase in the amount of the NR2C subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor and a decrease in the level of nNOS was detected in the locus coeruleus of depressed subjects (Karolewicz B. et al., Neuropsychopharmacology, 2005; Karolewicz et al., Journal of Neurochemistry, 2004).
Furthermore, our recent observations from the regions which have been traditionally held to be relevant to the neurobiology of depression, such as amygdala and hippocampus, provide first evidence of elevated levels of the NMDA receptor scaffolding protein (PSD-95) in subjects diagnosed with major depression as compared to psychiatrically healthy controls. Additionally, the overall level of the NR2A subunit of the NMDA receptor was modestly elevated in the lateral amygdala (Karolewicz et al. 2006, in preparation) among the same depressed subjects compared to controls.
Implications: Our data indicate that glutamatergic signaling at the NMDAR is abnormal in depression. Higher levels of NMDAR subunits and its scaffolding postsynaptic density proteins may represent an adaptive response to decreased stimulation by glutamate that may occur in depression. This hypothesis is in agreement with other postmortem and neuroimaging findings of altered glutamatergic transmission in depression. Further study of the glutamatergic system in depression will lead to a better understanding of the role of glutamate in the pathology of depression and may lead to the development of novel therapeutic approaches for the treatment of depressive disorders.