No abstract

Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-D-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the molecular pathology seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. mTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E, eIF4B). In this study, we examined the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examined. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant reduction in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were observed in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.

Both GABA synthesis and reuptake appear to be altered at the level of gene expression in a subset of GABA neurons, and the resulting changes in GABA neurotransmission may contribute to prefrontal cortex dysfunction in schizophrenia.

Background-Alteration of glutamatergic neurotransmission in the prefrontal cortex (PFC) may contribute to the pathophysiology of alcoholism and major depressive disorder (MDD). Among glial cells, astrocytes are mostly responsible for recycling synaptic glutamate by uptake through excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), and conversion to glutamine with glutamine synthetase (GS). Low density of astrocytes in the PFC of "uncomplicated' alcoholics and MDD subjects may parallel altered glutamate transporters and GS in the PFC.Methods-Immunohistochemistry and Western blotting for glutamate transporters, GS and glial fibrillary acidic protein (GFAP) were applied to postmortem tissue of the left orbitofrontal cortex from 13 subjects with MDD, 13 with alcoholism, 10 with comorbid alcoholism plus MDD (MDA), and 13 non-psychiatric controls. Area fraction of immunoreactivity was measured in sections, and protein levels in Western blots.Results-EAAT2 immunoreactivity was significantly lower in MDD and MDA subjects than in controls. EAAT1 levels were lower in MDA and MDD subjects as compared to controls, while GS levels in MDA were significantly lower than in alcoholics and controls, and lower in MDD subjects than in alcoholics. Area fraction of GFAP was lower in MDD, but not in MDA subjects as compared to controls or alcoholics.Limitations-High variability of protein levels in some groups and effects of antidepressant treatment, although appearing to be limited, cannot be fully evaluated.Conclusions-There are differential changes in the expression of glial glutamatergic markers in depression and alcoholism, suggesting a depletion of certain aspects of glutamatergic processing in depression.