cAMP/PKA/CREB

As mentioned, the delayed efficacy of monoaminergic antidepressants suggests a mechanism of action that is not simply explained by a restoration of a “chemical imbalance” via reuptake inhibition. As early as the 1980s, several preclinical investigators examined the vital role of intracellular second messenger/signal transduction cascades in the pathophysiology and treatment of depression. This examination was led by the discovery that antidepressants elicit their intracellular effects through canonical second messenger systems. Elevated synaptic levels of serotonin and norepinephrine activate cognate postsynaptic seven-transmembrane G-protein coupled receptors. Norepinephrine-induced β₁AR and β₂AR and serotonin-induced 5-HT₄, 5-HT₆, and 5-HT₇ receptor activation are predominantly implicated (Figure 1).Reference Sleight, Carolo, Petit, Zwingelstein and Bourson^1, Reference Svenningsson, Tzavara and Witkin² The intracellular domain of G-protein coupled receptors interacts with G_s/_i, which, through their α subunit, stimulates/inhibits adenylyl cyclase (AC). AC converts ATP-to-cAMP, which activates protein kinase A (PKA).

Figure 1 Canonical signal transduction cascades in preclinical models of despair and major depressive disorder. On the left side of the figure, monoamine neurotransmitter binding to cognate receptors recruits G protein adapters to their intracellular C-terminal tail. This activates (G_s)/inhibits (G_i) the cAMP/PKA/CREB cascade. Adenylyl cyclase converts ATP-to-cAMP, which stimulates protein kinase A to phosphorylate CREB. Phospho-CREB translocates to the nucleus to stimulate transcription of target genes involved in neuroprotection, neurotransmission, and cytoskeletal dynamics. On the right, neurotrophins bind to their cognate receptor tyrosine kinases and induce the autophosphorylation of their intracellular domain(s). This recruits numerous adapter proteins to the plasma membrane and stimulates protein–protein interactions that culminate in the activation of Raf, a protein kinase. Raf activates the small molecule Ras to induce mitogen-activated protein kinase (MAPK). Like the cAMP/PKA/CREB cascade, the MAPK/ERK pathway culminates in nuclear translocation of transcription factors (including CREB) to the nucleus. There is also cross-talk between these two cascades (as depicted in the middle of the figure) via phosphoinosotides leading to Akt activation. Akt phosphorylates GSK-3β, which dissociates it from Axin and APC (“degradation complex”). This stabilizes β-catenin and facilitates its nuclear translocation. Please refer to the accompanying text for a discussion of intracellular second messenger/signal transduction aberrations in depression, normalizing responses with antidepressants, and experimental targets for future drug development. βAR, beta-adrenergic receptor; 5-HT, 5-hydroxytryptamine (serotonin); DR, dopamine receptor; Trk, tyrosine kinase; NT, neurotrophin; Flk [VEGF (vascular endothelial growth factor) receptor], fetal liver kinase; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PDE, phosphodiesterase; CREB, cAMP-response element binding protein; LEF/TCF, lymphoid enhancer factor/T-cell factor; PP2A, protein phosphatase 2A; β-Arr, beta-arrestin; GSK-3β, glycogen synthase kinase-3 beta; APC, adenosis polyposis coli; β-Cat, beta-catenin; SHC, Src homology-2 domain containing (protein); Grb2, growth factor receptor-bound (protein) 2; Sos, son of sevenless; Ras, rat sarcoma; GTP, guanine triphosphate; GDP, guanine diphosphate; MAPKK, mitogen-activated protein kinase kinase; ERK, extracellular-regulated kinase.

AC activity is increased with both chronic antidepressant treatmentReference Menkes, Rasenick, Wheeler and Bitensky³ and electroconvulsive seizures (ECS).Reference Ozawa and Rasenick⁴ PKA phosphorylates downstream effector proteins involved in cytoskeletal reorganization and transcription. Standard antidepressants also increase PKA activity in fractionated rat necortex.Reference Ozawa and Rasenick^4, Reference Nestler, Terwilliger and Duman⁵ The cAMP-response element binding (CREB) protein is the major transcription factor responsible for neurotrophic/protective mRNA transcription in this cascade. Like PKA, chronic antidepressants increase CREB mRNA and protein levels in the rat hippocampus.Reference Nibuya, Nestler and Duman⁶ This increases expression of brain-derived neurotrophic factor (BDNF), especially in the hippocampal dentate gyrus.Reference Conti, Cryan, Dalvi, Lucki and Blendy⁷ Transgenic CREB overexpression in the hippocampus has antidepressant-like effects in rodent models of despair, and phospho-CREB (the activated isoform) stimulates CRE-responsive gene expression with chronic antidepressant treatment.Reference Thome, Sakai and Shin⁸

Due to aberrancies corrected by standard antidepressants, phosphodiesterase (PDE) dysfunction has been investigated in MDD. There are numerous PDE isoforms that have variable specificity for cAMP and cGMP; PDE4 is a brain-specific, cAMP-selective isoform that has been the most extensively studied in depression.Reference Zhang⁹ As displayed by [¹¹C]-rolipram positron emission tomography (PET), PDE4 levels are globally decreased (about 20% reduction in MDD).Reference Fujita, Hines and Zoghbi¹⁰ As a result, PDE inhibitors have been proposed as rational therapeutic targets. An inhibitor of PDE4, (RS)-4-[3-(cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidin-2-one (rolipram), has antidepressant effects in both MDDReference Fleischhacker, Hinterhuber and Bauer¹¹ and rodent models of despair.Reference Fujimaki, Morinobu and Duman^12, Reference Itoh, Tokumura and Abe¹³ Our group is currently studying changes in PDE4 levels after a treatment course with the selective serotonin reuptake inhibitor (SSRI) citalopram as a potential biomarker of treatment response (ClinicalTrials.gov identifier: NCT00369798). Even though there have been no additional trials with rolipram for two decades due to severe nausea, several pharmaceutical companies have subtype-specific, better-tolerated PDE inhibitors in their armamentarium for potential testing as antidepressants.

Neurotrophins

Centrally acting neurotrophins bind cognate receptors and intracellularly activate their tyrosine kinase domain, which induces autophosphorylation and recruits adapter proteins (Figure 1). In one of the most well-studied intracellular cascades in neuroscience, BDNF binds to TrkB, which activates the following three cascades: (1) extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), (2) phospholipase Cγ(PLCγ)/inositol triphosphate (IP₃), and (3) phosphatidylinositol-3 kinase (PI3 K) (as shown in Figure 1, except the PLCγ/IP₃ cascade). In the ERK/MAPK cascade, TrkB autoactivation recruits several adapter proteins: Shc, Grb2, and Sos. Sos is a guanine nucleotide exchange factor that converts GDP into the more energetically rich GTP. This sequentially activates Ras and Raf, the first protein kinase in this cascade. Like PKA, the activation of ERK/MAPK stimulates the transcription of target genes responsible for cytoskeletal rearrangement, neurotransmitter secretion, reuptake, etc.

The most extensively studied neurotrophin in depression is BDNF (reviewed by Tanis and DumanReference Tanis and Duman¹⁴). In brief, multiple stress-induction paradigms decrease hippocampal BDNF expression and cause depression-like behaviors.Reference Duman and Monteggia¹⁵ Antidepressant medications and electroconvulsive seizures (ECS) restore BDNF mRNA levels in the frontal cortex and hippocampus.Reference Nibuya, Morinobu and Duman^16, Reference Russo-Neustadt, Beard and Cotman¹⁷ Exogenous administration of BDNF into the midbrainReference Siuciak, Lewis, Wiegand and Lindsay¹⁸ and hippocampusReference Shirayama, Chen, Nakagawa, Russell and Duman¹⁹ also has antidepressant-like effects. Conditional BDNF knockout in the mouse forebrain impairs the antidepressant effects of desipramine on the forced swim test (FST).Reference Monteggia, Barrot and Powell²⁰ As a result, CNS BDNF expression is both necessary (based on inducible knockout experiments) and sufficient (from exogenous administration experiments) for antidepressant efficacy.

Vascular endothelial growth factor (VEGF) is another neurotrophin that has been investigated in depression. Stress decreases hippocampal VEGF levels.Reference Heine, Zareno, Maslam, Joels and Lucassen²¹ ECS restores VEGF expression and intracellular flux through its cognate receptor, Flk-1 (VEGFR2), via the proliferation of neural stem cells in the dentate gyrusReference Segi-Nishida, Warner-Schmidt and Duman²² and recruitment of constituents of the mTORC1 signaling pathway.Reference Elfving and Wegener²³ VEGF/Flk-1 signaling is also essential for the antidepressant effects of the SSRI fluoxetine.Reference Greene, Banasr, Lee, Warner-Schmidt and Duman²⁴ Next, exercise-induced alleviation of depression-like symptoms in rodents also activates VEGF/Flk-1.Reference Elfving and Wegener²³ In a rodent transgenic system (upregulation of cAMP through an Aplysia G_s-coupled receptor), VEGF was necessary for an antidepressant-like effect in several stress-induction paradigms.Reference Lee, Jang and Lee²⁵ In clinical studies, low plasma VEGF levels have been observed in suicide completers,Reference Isung, Mobarrez, Nordstrom, Asberg and Jokinen²⁶ and the antidepressant effects of total sleep deprivation coincide with increased plasma levels of VEGF.Reference Ibrahim, Duncan and Luckenbaugh²⁷ In a combined cohort of subjects in a current major depressive episode (both unipolar and bipolar depression), higher pretreatment VEGF levels trended in antidepressant responders versus nonresponders (p = 0.055).Reference Halmai, Dome and Dobos²⁸ Peripheral VEGF levels also remained elevated up to 1 month after a successful course of ECT.Reference Minelli, Zanardini and Abate²⁹ On a genetic level, the VEGF C/A polymorphism is associated with treatment-resistant depression (TRD), as the CC genotype is more common in ECT-treated patients than in controls (31.1% and 18.7%, respectively).Reference Viikki, Anttila and Kampman³⁰ However, another pharmacogenetic study revealed no association of seven different VEGF polymorphisms and antidepressant response.Reference Tsai, Hong and Liou³¹

Insulin-like growth factor-1 (IGF-1) has also been studied in depression. IGF-1 is produced by neuroendocrine cells in response to circulating hormones, especially growth hormone (GH) and insulin, and has potent mitogenic effects.Reference Clemmons³² Although initial clinical reports demonstrated increased IGF-1 levels in depressed patients,Reference Lesch, Rupprecht, Muller, Pfuller and Beckmann^33, Reference Deuschle, Blum and Strasburger³⁴ these investigations only examined peripheral levels (which may not accurately reflect centrally acting IGF-1) and did not discern between free and bound IGF-1.Reference Weber-Hamann, Blum and Kratzsch³⁵ As a result, several preclinical research groups have clarified the role of centrally acting IGF-1 and its inhibition. IGF-1 knockdown in CA1 hippocampal pyramidal neurons has depressogenic effects.Reference Mitschelen, Yan and Farley³⁶ Intracerebroventricular administration of IGF-1 and a non-selective IGF binding protein (which sequesters IGF-1 into a biologically inert complex) inhibitor have antidepressant and anxiolytic-like effects in stress induction paradigms.Reference Malberg, Platt and Rizzo³⁷ Central IGF-1 also decreases expression of proinflammatory cytokines, which may mitigate neuroinflammatory cascades that are critical in depression onset and/or maintenance.Reference Park, Dantzer, Kelley and McCusker^38, Reference Park, Lawson, Dantzer, Kelley and McCusker³⁹ Peripheral administration of an IGF-1 antibody blocks the antidepressant effects of exercise in a murine model of chronic unpredictable stress.Reference Duman, Schlesinger and Terwilliger⁴⁰ Back in the clinic, antidepressant treatment increased low CSF levels of IGF-1Reference Schilling, Blum and Heuser⁴¹; as a result, exogenous immediately acting (intranasal) IGF-1 is being investigated for the treatment of MDD.Reference Paslakis, Blum and Deuschle⁴²

Due to the discovery of decreased glial cell numbers in rodent models of despair and MDD,Reference Rajkowska and Miguel-Hidalgo⁴³ several groups have investigated a putative role for glial-derived neurotrophic factor (GDNF) in depression. MDD patients display an age-dependent decrease in peripheral GDNF levels,Reference Diniz, Teixeira and Miranda^44, Reference Tseng, Lee and Lin⁴⁵ which increases in response to treatmentReference Zhang, Zhang and Sha^46, Reference Liu, Zhu and Li⁴⁷ and normalizes during remission.Reference Otsuki, Uchida and Watanuki⁴⁸ In contrast, in a postmortem sample of recurrent depression, increased GDNF levels in parietal cortex were evident. Finally, in a study of rat glioma cells, antidepressant-induced GDNF expression/secretion was mediated by β-arrestin-1/CREB transcription complex formation,Reference Golan, Schreiber and Avissar⁴⁹ and GDNF epigenetic regulation (promoter methylation and histone modification) had adaptive effects in stressed mice.Reference Uchida, Hara and Kobayashi⁵⁰

Other centrally expressed neurotrophins, eg, nerve growth factor (NGF) and neurotrophin-3 (NT-3) and their cognate receptors TrkA, TrkC and p75NTR, are also under investigation in preclinical/clinical studies.

p11

p11 was initially found in a yeast two-hybrid screen as a 5-HT_1B and 5-HT₄ interactor.Reference Svenningsson, Chergui and Rachleff⁵¹ p11 mRNA and 5-HT_1B receptor transcripts co-express in several brain areas salient for depression.Reference Anisman, Du and Palkovits⁵² p11 mRNA was compared in helpless H/Rouen mice (a genetic model of depression) versus non-helpless NH/Rouen mice, and, at baseline, p11 mRNA levels were decreased in the forebrain in the helpless H/Rouen mice.Reference Svenningsson, Chergui and Rachleff⁵¹ The antidepressants imipramine and tranylcypromine as well as ECS increase neocortical p11 mRNA levels.Reference Svenningsson, Chergui and Rachleff⁵¹ p11 knockout mice display biochemical, electrophysiological, and behavioral responses consistent with depression.Reference Svenningsson, Chergui and Rachleff⁵¹ Furthermore, the antidepressant effects of imipramine in p11^−/− mice were reduced in these mice, and, when exposed to tail suspension and FST, they were more resistant to the antidepressant effects of exogenous BDNF.Reference Warner-Schmidt, Chen and Zhang⁵³ The transgenic overexpression of p11, on the other hand, increases resiliency to exogenous stress. BDNF increases p11 expression in a trkB and MAPK-dependent manner.Reference Warner-Schmidt, Chen and Zhang⁵³ Therefore, p11 is both necessary in the pathogenesis and sufficient for reversal of depressive behaviors.

The expression of p11 mRNA has also been examined in depressed suicide completers, which revealed downregulation in the anterior cingulate cortex relative to non-depressed controls.Reference Anisman, Du and Palkovits⁵² Prefrontal p11 mRNA is also decreased in suicide completers relative to postmortem controls.Reference Zhang, Su and Choi⁵⁴ Peripheral p11 mRNA levels are also decreased in suicidal attempters with comorbid MDD and posttraumatic stress disorder (PTSD) relative to non-attemptersReference Zhang, Su and Choi⁵⁴ (but increased relative to PTSD alone and healthy volunteers in another sampleReference Su, Zhang and Chung⁵⁵).

In non-human primates, chronic treatment with fluoxetine significantly increased p11 in peripheral mononuclear cells temporally consistent with antidepressant onset (unpublished personal communication from R. Innis, MD, PhD, NIMH). To translate these findings into humans, our group is presently investigating if peripheral p11 levels increase in response to successful SSRI treatment as a potentially biologically salient biomarker of treatment response (ClinicalTrials.gov identifier: NCT00697268).

Wnt/Fz/Dvl/GSK-3β

The Wnt/frizzled/disheveled/glycogen synthase kinase-3 beta cascade has been studied in the pathophysiology and therapeutics of depression (Figure 2). (Of note, GSK-3β can also be activated by PI3 K and Akt; for a review, see Voleti and Duman.)Reference Voleti and Duman⁵⁶ In the canonical signal transduction cascade, Wnt binding to Fz recruits a low-density lipoprotein receptor–related protein (LRP)5/6 to the plasma membrane, which interacts with the scaffolding protein disheveled. Disheveled mediates GSK-3β phosphorylation, which inactivates it. This releases β-catenin from the axin-adenosis polyposis coli-GSK-3β “destruction complex” for nuclear translocation.Reference Stamos and Weis⁵⁷ Nuclear β-catenin interacts with the transcription factor T-cell factor/lymphoid enhancer factor (TCF/LEF) to express Wnt-responsive genes.

Figure 2 Canonical Wnt/Fz/Dvl/GSK-3β signal transduction cascade. Wnts are secreted glycoproteins that are agonists for Fz receptors. Fz receptor stimulation recruits LRP to the plasma membrane, which may be inhibited by cytosolic isoforms of Dkk. The Wnt-Fz ligand-receptor complex recruits the scaffolding protein Dvl, which, in turn, stimulates Ca²⁺-dependent and Ca²⁺-independent pathways. The Ca²⁺ dependent pathway activates, among other mediators, PKC and CAMKII. In addition to their more notorious effects on phosphoinositides, PKC crosstalk with the MAPK/ERK cascade promotes neuromodulatory gene transcription (as depicted in Figure 1). CAMKII binds Ca²⁺ and stimulates neuromodulatory gene transcription through CREB. In the Ca²⁺ independent arm, Dvl stimulates phosphorylation of GSK-3β (as described in Figure 1) and facilitates dissociation of the β-catenin degradation complex and β-catenin mediated gene transcription. Please refer to the accompanying text for a discussion of aberrations in depression, normalizing responses with successful antidepressant treatment, and potential experimental targets for future investigation. Fz, frizzled; LRP, low-density lipoprotein receptor-related protein; Dkk, Dickkopf; Dvl, disheveled; PKC, protein kinase C; MAPK, mitogen activated protein kinase; ERK, extracellular-regulated kinase; CAMKII, calcium-calmodulin dependent protein kinase II; CREB, cAMP-response element binding protein; LEF/TCF, lymphoid enhancer factor/T-cell factor; GSK-3β, glycogen synthase kinase-3 beta; APC, adenosis polyposis coli; β-Cat, beta-catenin.

The Wnt/Fz/Dvl/GSK-3β cascade has been implicated in neuromodulation, especially synapse formation, neurotransmission, and cytoskeletal reorganization.Reference Inestrosa and Arenas⁵⁸ The expression of an endogenous Wnt inhibitor, Dickkopf-1 (Dkk-1), is increased with mild restraint stress and exogenous corticosterone administration.Reference Matrisciano, Busceti and Bucci⁵⁹ Mice lacking the Dkk1 transcriptional enhancer (Doublridge mice) are more resilient to chronic unpredictable stress.Reference Matrisciano, Busceti and Bucci⁵⁹ Another isoform, Dickkopf-2 (Dkk2), is downregulated by chronic ECS.Reference Voleti, Tanis, Newton and Duman⁶⁰ In this same study, a frizzled receptor isoform, Fz6, was increased by chronic ECSReference Voleti, Tanis, Newton and Duman⁶⁰ and demonstrated that viral vector-mediated inhibition of Fz6 was anxio- and depressogenic in numerous behavioral paradigms.

GSK-3β is a serine-threonine kinase that has been extensively investigated in psychotic and mood disorders, especially bipolar disorder after the discovery that lithium is a potent GSK-3β inhibitor.Reference Machado-Vieira, Manji and Zarate⁶¹ In preclinical models of despair, the heterozygous deletion of GSK-3β has antidepressant effects, and GSK-3 inhibitors (L803-mts and AR-A014418) mimicked these genetic effects.Reference Voleti, Tanis, Newton and Duman^60, Reference Gould, Einat, Bhat and Manji^62, Reference O'Brien, Harper and Jove⁶³ The phosphorylation of GSK-3β is increased by chronic administration of the antidepressants fluoxetine or venlafaxine.Reference Okamoto, Voleti and Banasr⁶⁴ A depressive phenotype was also observed with overexpression of GSK3β in the NAcc, while a dominant-negative GSK3β isoform promoted resiliency.Reference Wilkinson, Dias and Magida⁶⁵

Several other pathway intermediates are affected by antidepressant therapy. Wnt2 was increased by several antidepressants (including ECS) in a microarray study of a rodent model of despair.Reference Okamoto, Voleti and Banasr⁶⁴ Additionally, Wnt2 transgenic overexpression in the hippocampus was sufficient to generate antidepressant-like effects.Reference Okamoto, Voleti and Banasr⁶⁴ Wnt7b expression, on the other hand, was increased by atomoxetine and ECS.Reference Okamoto, Voleti and Banasr⁶⁴ Fz9 levels were upregulated by the noradrenergic antidepressants atomoxetine and venlafaxine but not by SSRIs.Reference Okamoto, Voleti and Banasr⁶⁴ Blockade of a disheveled isoform, Dvl2 [via both overexpression of a dominant-negative isoform and intra-nucleus accumbens (NAcc) inhibitor infusion], decreased resiliency to social defeat and other modalities for inducing despair.Reference Wilkinson, Dias and Magida⁶⁵

To our knowledge, there have been no CNS-penetrant small molecule modulators of the Wnt/Fz/Dvl/GSK-3β pathway that have been tested in psychiatric disorders. We seek translation of these interesting rodent findings into the pathophysiology and experimental therapeutics of MDD. Due to this signal transduction/second messenger system's involvement in numerous cellular pathways, especially mitogenesis, translational studies will need to pay close attention to toxicity and side effect profiles.

NF-kB/ΔFosB

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a transcription factor that has been most extensively studied in immunology but also plays a functional role in synaptic processes underlying learning and memory.Reference Meffert and Baltimore⁶⁶ After demonstrating its function in instrumental and other forms of motivated learning, several groups have investigated NF-κB induction of ΔFosB, a truncated version of the immediate-early transcription factor FosB, in rodent models of despair. Lipopolysaccharide-exposed rodents have a delayed increase in immunostaining for ΔFosB that parallels the onset of increased immobility on the FST and reduced sucrose consumption (a preclinical marker of anhedonia).Reference Frenois, Moreau and O'Connor⁶⁷ Serum response factor (SRF), another transcription factor, decreases ΔFosB in the NAcc in response to chronic social defeat.Reference Vialou, Maze and Renthal⁶⁸ SRF levels are also decreased in the NAcc in chronic social defeat stress in mice and unipolar depression.Reference Vialou, Maze and Renthal⁶⁸ In addition, genetic deletion of NAcc SRF decreased resiliency to stress.Reference Vialou, Maze and Renthal⁶⁸

Several studies have demonstrated that ΔFosB expression correlates with antidepressant-like effects.Reference McClung, Ulery and Perrotti⁶⁹ In an elegant study using different mouse strains genetically engineered to produce FosB +/− ΔFosB, the ΔFosB haplotype (+/Δ) strain had increased depressive-like behaviors relative to wild-type and the double knock-in (Δ/Δ), which displayed less anxiety in the open field test.Reference Ohnishi, Ohnishi and Hokama⁷⁰ ΔFosB expression increased in multiple rat brain regions, eg, dorsal raphe nucleus, frontal cortex, hippocampus, and basolateral amygdala, with standard antidepressants (sertraline and desipramine) and vagal nerve stimulation (VNS).Reference Furmaga, Sadhu and Frazer⁷¹ Interestingly, VNS appeared to have a larger effect and affected some brain regions not observed with traditional antidepressants (nucleus tractus solitarius and locus ceruleus).Reference Furmaga, Sadhu and Frazer⁷¹

mTOR

As the activation of intracellular neuromodulatory cascades is critical for the mechanism of action of standard antidepressants, several recent studies have elucidated the mechanisms underlying the rapidly acting antidepressant effects of glutamate-based medications such as ketamine. Li etal. Reference Li, Lee and Liu⁷² discerned that the activation of mammalian target of rapamycin (mTOR) was necessary for ketamine's antidepressant effects (Figure 3). A case report in a single treatment-resistant depressed patient revealed that intravenous ketamine increased peripheral mTOR expression on a time course that coincided with its rapid antidepressant effects.Reference Denk, Rewerts, Holsboer, Erhardt-Lehmann and Turck⁷³ Like ketamine, the proprietary mGluR2/3 antagonist, LY341495, rapidly (within 1 h) activated mTOR and downstream pathway constituents (p70S6K, 4E-BP1) and subsequently (24 h later) increased levels of postsynaptic density proteins (PSD-95, GluR1, synapsin I).Reference Dwyer, Lepack and Duman⁷⁴ These antidepressant effects of LY341495 were reversed by the mTOR inhibitor rapamycin.Reference Dwyer, Lepack and Duman⁷⁴

Figure 3 Signal transduction cascades activated by the rapidly-acting antidepressant ketamine. Based on preliminary preclinical and unpublished clinical data, postsynaptic NMDA receptor antagonism incites a rapid presynaptic glutamate surge. Glutamate then stimulates AMPA receptors. AMPA potentiation increases Na+ to induce the phosphorylation of mTOR, a central signaling hub that has multiple downstream effectors. Activated mTOR then phosphorylates p70S6K. Phospho-p70S6K can directly stimulate translation of downstream postsynaptic targets. Stimulated mTOR also inhibits 4E-BP, thereby relieving translational inhibition. NMDA receptor activation also inhibits eEF2K, which increases levels of dephosphorylated eEF2. Dephosphorylated eEF2 relieves inhibition of BDNF translation in dendritic spines. This multitiered translational activation increases the expression of neuromodulatory proteins involved in, among other effects, postsynaptic scaffolding, neurotransmitter dynamics, and dendritic spine morphogenesis (from synaptically unstable filipoda to synaptically dynamic mushroom-shaped spines, which form the morphological substrate for diverse neuropsychiatric responses: learning, memory, and, most importantly here, antidepressant-like behavioral effects). Through its release of inhibition on local translation, ketamine also increases excitatory postsynaptic potentials in prefrontal cortical neurons. NMDA, N-methyl-D-aspartate; AMPA, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid; mTOR, mammalian target of rapamycin; 4E-BP, eukaryotic initiation factor 4E-binding protein; eEF2, eukaryotic elongation factor 2; eEF2K, eEF2 kinase; FKBP12, FK506-binding protein 12; LST8, mammalian lethal with sec 13; PI3K, phosphoinositide-3 kinase; mTORC1, mTOR complex 1; PRAS40, proline-rich Akt/PKB substrate of 40 kD; p70S6K, p70 S6 kinase. T = threonine, S = serine (with trailing number denoting the phosphorylated residue).

eEF2K/CAMKIII

Finally, the release of inhibition on local translation in dendritic spines has emerged as an exciting intracellular target of ketamine. Autry etal. Reference Autry, Adachi and Nosyreva⁷⁵ reported that subanesthetic doses of ketamine released inhibition of translation by deactivating eukaryotic elongation factor 2 kinase (eEF2K)/calcium-calmodulin protein kinase type III (CAMKIII) (Figure 3). The ensuing dephosphorylation of eEF2 removes tonic inhibition on BDNF translation in the hippocampus, thereby increasing BDNF levels and concomitant TrkB receptor activation. The deactivation of eEF2K and stimulation of eEF2 (thereby increasing central BDNF levels) has emerged as a novel rational therapeutic target in MDD.Reference Monteggia, Gideons and Kavalali⁷⁶