Progress in Neuro-Psychopharmacology and Biological Psychiatry
The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder
Research highlights
► We used postmortem cortical tissue to examine mTOR signaling in depression. ► Reductions in mTOR, p70S6K, eIF4B and p-eIF4B were identified. ► No differences were seen in eIF4E, p-eIF4E or actin levels. ► Specific dysregulation of mTOR/p70S6K/eIF4B signaling is evident in depression. ► Dysfunction of mTOR signaling may underlie synaptic deficits in depression.
Introduction
A major limitation of established antidepressants is the delayed onset of therapeutic response, resulting in non-compliance and dramatically increased risk for suicidal behavior. Of particular relevance is the demonstration that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, induced a rapid (within hours), long lasting (up to 1 week), and robust antidepressant effect in treatment-resistant cases of MDD (Berman et al., 2000, Zarate et al., 2006). Recent animal studies indicate that the fast antidepressant response to NMDA receptor antagonists (ketamine and Ro 25–6981) is mediated by rapid activation of the mammalian target of rapamycin (mTOR) pathway leading to an increase in synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex (PFC) of rats (Li et al., 2010). Moreover, it has been demonstrated that a single dose of these antagonists rapidly reversed the chronic stress-induced behavioral and synaptic deficits in an mTOR-dependent manner (Li et al., 2011). Our recent postmortem studies show significant reductions in the expression of prominent postsynaptic proteins involved in glutamate neurotransmission, including NMDA receptor subunits (NR2A and NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density 95 kDa (PSD-95) in the PFC from depressed subjects (Deschwanden et al., 2011, Feyissa et al., 2009). These studies may indicate an association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD (Karolewicz et al., 2011).
Traditionally, it was thought that the change in the proteome is caused by transcriptional activity. Now it is known that regulation of translation is another way of altering protein production (Nilsson et al., 2004). Protein synthesis is a highly regulated process that can be separated into three general phases: initiation, elongation and termination (Hoeffer and Klann, 2010, Klann et al., 2004). The rate-limiting step in the process of protein synthesis is translation initiation (Hoeffer and Klann, 2010, Holz et al., 2005). The activity of mTOR, an ubiquitously expressed serine/threonine kinase, is central to the regulation of translation initiation and, consequently, protein synthesis required for long-term potentiation and new synaptic connections (Hashimoto, 2011, Hoeffer and Klann, 2010, Klann et al., 2004, Tang et al., 2002, Tang and Schuman, 2002).
It has been reported that neuronal mTOR function is influenced by the activity of growth factors, insulin, cytokines, as well as glutamate activity via NMDA receptors and metabotropic glutamate receptors (mGluR) (Antion et al., 2008, Gong et al., 2006, Hay and Sonenberg, 2004, Hoeffer and Klann, 2010) (Fig. 1). Activated mTOR phosphorylates p70-kDa ribosomal protein S6 kinase (p70S6K) followed by p70S6K-induced phosphorylation of eukaryotic initiation factor 4B (eIF4B) which promotes the initiation of protein translation (Raught et al., 2004). mTOR also phosphorylates and inactivates eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), reducing its affinity for eIF4E and releasing eIF4E to facilitate translation initiation. Activated translation initiation factors, particularly eIF4E and eIF4B, are responsible for ribosome recruitment to the 5′ end of mRNA. The 5′ end of all nuclear-transcribed mRNAs possess a cap structure (m7GpppN, in which “m” represents a methyl group and “N”, any nucleotide) that is specifically recognized by eIF4E. Thus, eIF4E guides the ribosome to an mRNA 5′ end and facilitates its binding. On the other hand, eIF4B potentiates ribosome recruitment by stimulating the helicase activity of the eukaryotic initiation factor 4A (eIF4A), to unwind mRNA secondary structure for efficient translation (Gingras et al., 1999, Hay and Sonenberg, 2004, Holz et al., 2005, Rogers et al., 2002). Thus, mTOR controls the efficiency of protein translation within cells via its critical downstream targets (Fig. 1).
There is abundant evidence linking mTOR signaling to synaptic plasticity, memory, neurological disorders, and cancer (Gong et al., 2006, Hay and Sonenberg, 2004, Hoeffer and Klann, 2010). To date there are no studies that implicate the mTOR signaling pathway in the pathology of MDD. We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the molecular pathology seen in the PFC in MDD. Therefore, the goal of this study is to examine MDD-related changes in the protein level of mTOR and its downstream signaling targets: p70S6K, eIF4E, eIF4B in cortical tissue (PFC BA10) from the same MDD subjects as those used in our previous postmortem studies (Deschwanden et al., 2011, Feyissa et al., 2009). Additionally, levels of eIF4E phosphorylated at serine 209 (p-eIF4E Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B Ser504) were examined.
Section snippets
Human subjects
Postmortem brain samples were collected at autopsy at the Cuyahoga County Coroner's Office in Cleveland, OH. Informed written consent was obtained from the legal next-of-kin of all subjects. Next-of-kin were interviewed and retrospective psychiatric assessments were conducted in accordance with Institutional Review Board policies at Case Western Reserve University and the University of Mississippi Medical Center. A trained interviewer administered the Schedule for Affective Disorders and
Results
Amounts of mTOR, p70S6K, eIF4E, eIF4B, p-eIF4E (Ser209), and p-eIF4B (Ser504) were analyzed in the PFC BA10 from 12 pairs of subjects with MDD and matched healthy controls. Fig. 2 shows representative immunoblots from 3 pairs of subjects used in the analysis. The amount of mTOR immunoreactivity from depressed subjects (0.42 ± 0.06) was significantly lower compared to controls (0.616 ± 0.055; t = 4.13 df = 11, p = 0.0017, Fig. 3). Similarly, there was a robust reduction in the level of p70S6K in depressed
Discussion
The present study is the first to analyze levels of the mTOR-dependent translation initiation factors in the PFC from subjects diagnosed with MDD. Significant reductions in the expression of mTOR, p70S6K, eIF4B, and p-eIF4B were observed in MDD subjects as compared to psychiatrically healthy controls. In contrast, levels of eIF4E and p-eIF4E were unchanged in depressed subjects. Previously, we reported marked deficits in prominent postsynaptic proteins involved in glutamate neurotransmission
Acknowledgements
We thank Dr. Feyza Aricioglu for comments on the manuscript. The authors thank Drs. Dorota Maciag and Warren May for assistance in statistical analysis. We gratefully acknowledge the assistance of Drs James C Overholser, George Jurjus, Herbert Y Meltzer, and Ginny Dilley and Lisa Konick, MA, in the establishment of retrospective psychiatric diagnoses. The excellent assistance of the Cuyahoga County Coroner's Office, Cleveland, OH, is greatly appreciated. We thank the next-of-kin for their
References (29)
- et al.
Antidepressant effects of ketamine in depressed patients
Biol Psychiatry
(2000) - et al.
Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subjects
Biol Psychiatry
(2010) - et al.
Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression
Prog Neuropsychopharmacol Biol Psychiatry
(2009) - et al.
Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression
Prog Neuropsychopharmacol Biol Psychiatry
(2010) - et al.
Nosology of chronic mood disorders
Psychiatr Clin North Am
(1996) - et al.
Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons
J Biol Chem
(2006) - et al.
mTOR signaling: at the crossroads of plasticity, memory and disease
Trends Neurosci
(2010) - et al.
mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events
Cell
(2005) - et al.
Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims
Biol Psychiatry
(2007) - et al.
Glutamate N-methyl-d-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure
Biol Psychiatry
(2011)
eIF4A: the godfather of the DEAD box helicases
Prog Nucleic Acid Res Mol Biol
The effect of MK-801 on mTOR/p70S6K and translation-related proteins in rat frontal cortex
Neurosci Lett
Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction
Schizophr Res
mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K-deficient mice
Mol Cell Biol
Cited by (0)
- 1
Mrs. Jernigan and Dr. Goswami contributed equally to this article.