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, 35 (7), 1774-9

The mTOR Signaling Pathway in the Prefrontal Cortex Is Compromised in Major Depressive Disorder

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The mTOR Signaling Pathway in the Prefrontal Cortex Is Compromised in Major Depressive Disorder

Courtney S Jernigan et al. Prog Neuropsychopharmacol Biol Psychiatry.

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 95kDa (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 and eIF4B). In this study, we examined the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, and 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.

Figures

Figure 1
Figure 1
Simplified diagram illustrating the mTOR signaling pathway. Neuronal receptors (NMDAR, mGluR, and TrkB) activate downstream signaling pathways, including PDK1, leading to mTOR activation. Activated mTOR phosphorylates p70S6K followed by p70S6K induced phosphorylation of eIF4B which promotes the initiation of protein translation. mTOR also phosphorylates and inactivates eukaryotic 4E-BP1 reducing its affinity for eIF4E and releasing eIF4E to facilitate translation initiation. Abbreviations: NMDAR, N-methyl-D-aspartate receptor; mGluR, metabotropic glutamate receptor; PSD-95, postsynaptic density-95 kDa; TrkB, tyrosine kinase B receptor; PDK1, phosphoinositide-dependent kinase 1; mTOR, mammalian target of rapamycin; p70S6K, p70 kDa ribosomal protein S6 kinase; eIF4B, eukaryotic initiation factor 4B; 4E-BP1, eukaryotic initiation factor 4E binding protein 1; eIF4E, eukaryotic initiation factor 4E. Diagram drawn using information from Hoeffer and Klann (2010) and Klann et al. (2004).
Figure 2
Figure 2
Immunoblots of mTOR, p70S6K, eIF4E, p-eIF4E, eIF4B, p-eIF4B and actin from six representative subjects used in the analysis. Each well was loaded with 20ug of total protein. Cont, control; MDD, major depressive disorder.
Figure 3
Figure 3
Scatter plots of mTOR, p70S6K, eIF4E, and eIF4B protein levels normalized to actin. Significant reductions in mTOR, p70S6K, and eIF4B immunoreactivities were observed in depressed subjects (filled circles; n=12) as compared to controls (open circle; n=12). Normalized optical density values for the individual subjects and mean values (horizontal lines) are presented. A p-value <0.0083 was considered as a threshold for significance.
Figure 4
Figure 4
Scatter plots of p-eIF4E, and p-eIF4B protein levels normalized to actin. Significant reduction in p-eIF4B immunoreactivity was observed in depressed subjects (filled circles; n=12) as compared to controls (open circle; n=12). Normalized optical density values for the individual subjects and mean values (horizontal lines) are presented. A p-value <0.0083 was considered as a threshold for significance.

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