Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression.
Compelling evidence suggests that major depression is associated with dysfunction of the brain glutamatergic transmission, and that the glutamatergic N-methyl-d-aspartate (NMDA) receptor plays a role in antidepressant activity. Recent post-mortem studies demonstrate that depression is associated with altered concentrations of proteins associated with NMDA receptor signalling in the brain. The present study investigated glutamate signalling proteins in the amygdala from depressed subjects, given strong evidence for amygdala pathology in depression. Lateral amygdala samples were obtained from 13-14 pairs of age- sex-, and post-mortem-interval-matched depressed and psychiatrically healthy control subjects. Concentrations of NR1 and NR2A subunits of the NMDA receptor, as well as NMDA receptor-associated proteins such as post-synaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) were measured by Western immunoblotting. Additionally, levels of enzymes involved in glutamate metabolism, including glutamine synthetase and glutamic acid decarboxylase (GAD-67), were measured in the same amygdala samples. NR2A protein levels were markedly and significantly elevated (+115%, p=0.03) in depressed subjects compared to controls. Interestingly, PSD-95 levels were also highly elevated (+128%, p=0.01) in the same depressed subjects relative to controls. Amounts of NR1, nNOS, glutamine synthetase, and GAD-67 were unchanged. Increased levels of NR2A and PSD-95 suggest that glutamate signalling at the NMDA receptor in the amygdala is disrupted in depression.
Karolewicz
Beata
B
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. bkarolewicz@psychiatry.umsmed.edu
Szebeni
Katalin
K
Gilmore
Tempestt
T
Maciag
Dorota
D
Stockmeier
Craig A
CA
Ordway
Gregory A
GA
D000328:Adult; D000368:Aged; D000679:Amygdala / Q000378:metabolism*; D000704:Analysis of Variance; D003863:Depression / Q000473:pathology*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D011180:Postmortem Changes; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013223:Statistics as Topic / Q000379:methods
C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D052248:Nitric Oxide Synthase Type I; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1