Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders

Neuroscience and Biobehavioral Reviews 80 (2017) 555–572

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Review article

Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders

T

Mehdi Ghasemia, Cristy Phillipsb, Atoossa Fahimic,d, Margaret Windy McNerneyc,d, ⁎ Ahmad Salehic,d, a

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA Department of Physical Therapy, Arkansas State University, Jonesboro, AR, USA c VA Palo Alto Health Care System, USA d Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA b

A R T I C L E I N F O

A B S T R A C T

Keywords: NMDA receptor NMDA receptor antagonists Major depressive disorder Bipolar disorder Mood disorders Ketamine Glutamate BDNF Inflammation Norepinephrine Serotonin Ketamine

Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-D-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials. Altogether, these studies establish a warrant for the refinement of novel compounds that target glutamatergic mechanisms for the treatment of MDs.

1. Introduction Mood disorders (MDs) such as major depressive disorder (MDD) and bipolar disorder (BP) comprise chronic and debilitating psychiatric disorders that affect over 350 million persons worldwide (Brundtland, 2001; Merikangas et al., 2011). Characteristic of MDs is a constellation of disturbances that involve adverse thought processes, working memory impairments, and psychosomatic symptoms (e.g., changes in body weight, sleep routines, and energy levels) (Jick et al., 2004). Along with the tremendous human toll of MDs are significant socioeconomic burdens (Murray and Lopez, 1997; Kessler et al., 2005; Lepine and Briley, 2011). The World Health Organization estimates that MDs will become the second leading cause of disability and death by the year 2020 (Brundtland, 2001). Despite their devastating impact, the

heterogeneous mechanisms that underlie MDs have yet to be elucidated fully (Baumann et al., 1999). Early pharmacological exploration of MDs began following the serendipitous discovery that reserpine, a drug used for the treatment of hypertensive vascular disease, precipitated depression in a few patients, symptoms that reversed following termination of treatment, rest, or electric shock therapy (Muller et al., 1955). Further experimental analysis revealed that reserpine inhibited vesicular monoamine transporters and depleted central monoamine levels [i.e., serotonin (5-HT) and catecholamines], a fact that implicated serotonin and norepinephrine (NE) in MD pathobiology (Shore et al., 1955, 1957; Weiner et al., 1972). Later it was shown that administration of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants altered monoamine neurotransmitter levels and relieved depressive symptoms.

Abbreviations: AR, adrenergic receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPAR, AMPA receptor; BDNF, brain-derived neurotrophic factor; BP, bipolar disorder; CAMK, Ca2+/calmodulin-dependent protein kinase; CREB, cAMP response element-binding protein; eEF2, eukaryotic elongation factor 2; ERK, extracellular signal-regulated kinase; GABA, gamma-amino butyric acid; IL, interleukin; IFN, interferon; LTP, long-term potentiation; MDD, major depressive disorder; MAOIs, monoamine oxidase inhibitors; MDs, mood disorders; NE, norepinephrine; NF-κB, nuclear factor-κ; NMDA, N-methyl-D-aspartate; NMDARs, NMDA receptors; NT, neurotrophins; PKA, protein kinase A; PkC, protein kinase C; SSRI, selective serotonin reuptake inhibitors; 5-HT, 5-Hydroxytryptophan; TARPS, transmembrane AMPA receptor regulatory proteins; TNF, tumor necrosis factor; Trk, tropomyosin receptor kinase ⁎ Corresponding author at: Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA. E-mail address: [email protected] (A. Salehi). http://dx.doi.org/10.1016/j.neubiorev.2017.07.002 Received 13 February 2017; Received in revised form 23 June 2017; Accepted 8 July 2017 Available online 13 July 2017 0149-7634/ Published by Elsevier Ltd.

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Altogether, these findings prompted the hypothesis that monoamine depletion contributed to MD pathology (Bunney and Davis, 1965; Schildkraut, 1995; Delgado, 2000; Hirschfeld, 2000), a notion referred to as the monoamine hypothesis. Accordingly, therapeutic agents for MDs were derived to increase monoamine transmission acutely, either by inhibiting neuronal reuptake or by inhibiting degradation in the synaptic cleft. While this strategy has demonstrated some utility in alleviating symptoms, their slow pace of action (3–5 weeks), extensive side-effects, and poor response in a significant proportion of persons treated (65–75%) remain significant limitations (Manji et al., 2001; Oswald et al., 1972; Paul and Skolnick, 2003; Trivedi, 2006). Moreover, the fact that monoamine depletion fails to produce depressive symptoms in healthy individuals (Salomon et al., 1997) or worsen depressive symptoms in persons with MDD (Delgado et al., 1994; Berman et al., 2002) suggests that additional mechanisms and systems are involved in the pathophysiology of MDs. Currently, glutamate and glutamate-mediated activation of N-methyl-D-aspartate receptors (NMDARs) and associated subcellular calcium-dependent pathways are considered as viable therapeutic targets for several neuropsychiatric disorders. Supporting this notion is evidence that brain regions implicated in MD pathobiology are modulated by monoamine projections from midbrain and brainstem nuclei (serotonin from the dorsal raphe located in the periaqueductal grey area, and NE from the locus coeruleus). Furthermore, disruptions in these systems parallel NMDAR dysfunction (Auer et al., 2000; Michael et al., 2003; Mitani et al., 2006; Hashimoto et al., 2007; Frye et al., 2007; Walter et al., 2009; Finlay et al., 2015). Glutamatergic abnormalities occur in the blood (Altamura et al., 1993; Mitani et al., 2006) and cerebrospinal fluid (Frye et al., 2007) of persons with MDs. While a number of confounding factors in postmortem studies make it more difficult to interpret the results (Hashimoto et al., 2007), important information has been gained through these studies. Significant alterations have been reported in postmortem brain samples in both glutamate and NMDAR expression in patients with MDs (Choudary et al., 2005; Beneyto et al., 2007; Beneyto and Meador-Woodruff, 2008; Feyissa et al., 2009; Hashimoto, 2010; Sanacora and Banasr, 2013; Bernstein et al., 2015). For instance, a number of studies have shown increased brain glutamate levels in both MDD and BP (Hashimoto et al., 2007; Lan et al., 2009; Sanacora et al., 2012). As for the NMDARs, while decreased hippocampal NR1 and NR2A gene expression has been detected in both MDD and BP (Scarr et al., 2003; McCullumsmith and Sanacora, 2015) no alterations in NR1 activity have been found in either condition (Thompson et al., 2003; Toro and Deakin, 2005). A number of preclinical studies have demonstrated that several NMDAR antagonists exert antidepressant effects (Trullas and Skolnick, 1990; Paul and Skolnick, 2003) that appear to utilize mechanisms other than monoamine reuptake inhibitors. That is, NMDAR antagonists rapidly induce spine formation and, by corollary, may reverse the synaptic disconnection in the cortico-limbic circuit that is impaired in MDs (Hornung, 2003; Waselus et al., 2011; Duman, 2014). Evidence of these rapid effects creates an imperative to pursue novel treatments for MDs that target alternate neurobiological points of vulnerability and protection, particularly for patient groups that fail to respond to extant therapies. Awareness of the latter prompted us to focus on putative interactions between NMDAR signaling and neurobiological pathways (e.g., biogenic amines, trophic factors, and inflammation) that affect neuroplasticity by serving as a point of vulnerability or protection. Then we emphasize specific agents (ketamine, memantine, dextromethorphan, and MK-0657/RDPC) targeting the glutamatergic system that have demonstrated some efficacy in the treatment of MDs.

of mammals (Niciu et al., 2012), and binding sites for glutamate are abundantly localized in brain regions implicated in MD pathology. Upon release, glutamate can bind to NMDARs, tetrameric structures composed of 7 subunits including an obligatory GluN1 subunit along with various combinations of GluN2 and GluN3 subunits that differ according to anatomical distribution, developmental profile, and functional activity (Hynd et al., 2004; Benarroch, 2011). In addition to those for glutamate, there are multiple binding sites on NMDARs for glycine (D-serine), Mg2+, and other polyamines. Increasingly, it is thought that synaptic and extrasynaptic NMDARs play a vital role in the antidepressant efficacy of NMDA antagonists (Hardingham and Bading, 2010). The NMDA channel contains a Mg2+ plug that prevents ions from freely flowing through their channels under resting conditions. Yet adjacent α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors can depolarize the cell membrane and expel the Mg2+ plug from the channel when given a sufficient stimulus. This allows NMDARs to become responsive to glycine and glutamate binding and undergo a conformational change to permit the nonselective influx of Na+ and Ca2+ ions. Entering Ca2+ ions then act as secondary messengers to elicit several intracellular signaling cascades, including those that regulate monoaminergic activity, neurotrophin expression, dendritic development and neuronal growth, long-term potentiation (LTP), and cell–cell interactions (Johnson and Taniuchi, 1987; Chiu et al., 1999; Mothet et al., 2000; Ghasemi and Schachter, 2011; Ghasemi et al., 2014; Sanacora et al., 2008). However, excess glutamate levels disrupt glial transport of glutamate from the synapse, impair synaptic transmission and plasticity, and, ultimately, are excitotoxic to affected neurons, a mechanism putatively implicated in MD pathobiology (Bliss and Collingridge, 1993; Cacabelos et al., 1999; Cull-Candy and Leszkiewicz, 2004; Lau and Zukin, 2007; Hardingham and Bading, 2010). These processes make it seem plausible that the neuronal atrophy and disconnection in MD-related circuits co-occur with imbalances in synaptic and extrasynaptic NMDAR signaling caused by synapse loss, altered Ca2+ transduction signals from the synapse to the nucleus, or redistributions of NMDARs from synaptic to extrasynaptic sites. By corollary, the antagonistic signaling of synaptic and extrasynaptic NMDARs provides a novel method of approaching neuroprotective therapies. Below, we review the pathophysiologic aspects of NMDAR signaling in MDs in relation to neurotransmitter systems. 3. Modulators of NMDAR function Several molecules and brain circuits impose significant modulatory influence on NMDARs. Here we assess the nature and mechanisms of action of a few pharmacologically relevant modulators in MDs. 3.1. Serotonergic system In the late 1960s, the indoleamine hypothesis of MDs was proposed (Coppen et al., 1965; Lapin and Oxenkrug, 1969), wherein vulnerability to either depression or mania was related to low 5-HT-ergic system activity as a result of diminished 5-HT release, fewer 5-HT receptors, or impaired 5-HT receptor-mediated signal transduction. Prange et al. later formulated a permissive role for 5-HT where a central neurotransmission deficit contributed to the manic and depressive phases of BP (Prange et al., 1974). Accordingly, a number of antidepressants currently available in the market are designed to increase serotonergic transmission by inhibiting neuronal reuptake (e.g., selective serotonin reuptake inhibitors [SSRIs]) or inhibiting its degradation (e.g., MAOIs). More recently, the focus has been on understanding the relationship between 5-HT and NMDAR signaling. The first evidence of interactions between 5-HT and NMDARs was published in 1982 by Reisine et al. (Reisine et al., 1982). Using cats implanted with push-pull cannulae, these investigators demonstrated that administration of L-glutamic acid into either the caudate nucleus or

2. Glutamatergic system and NMDAR signaling Glutamate is the principal excitatory neurotransmitter in the brain 556

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anxiety-related behaviors (Drevets et al., 2007). 5-HT1A receptors are expressed in two distinct neuronal populations in the brain: (i) as somatodendritic autoreceptors on 5-HT-ergic neurons in the raphe nuclei of the brainstem and (ii) as heteroreceptors on non-5-HT-ergic neurons in forebrain structures (e.g., hippocampus, septum, and cortex). Activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus induced the opening of potassium channels, hyperpolarization of the membrane, and in turn, decreased firing of 5-HT neurons (Montalbano et al., 2015). Adaptation of these autoreceptors occurred through a desensitization process over the course of 2–3 weeks of SSRIs administration, allowing the recovery of 5-HT neurons to their normal firing rate in the presence of reuptake inhibition (Berman et al., 1997). Desensitization increased 5-HT transmission in projecting regions, particularly in the forebrain area involved in the regulation of mood and emotional behaviors. Evidence supporting the interaction between 5-HT heteroreceptors and NMDAR signaling has derived from several lines of study. It has been shown that the 5-HT1A receptor is a functional antagonist to glutamatergic receptor stimulation by mechanisms that involve blocking of NMDAR-mediated Ca2+ influx into neurons (Bielenberg and Burkhardt, 1990; Kishimoto et al., 1994; Strosznajder et al., 1994). In addition, the activation of 5-HT1A receptors by 5-HT-ergic neurons projecting from the dorsal raphe suppressed NMDAR currents via protein kinase A inhibition (Fig. 1), which diminished microtubule stability and GluN2B subunit trafficking along dendrites (Yuen et al., 2005). Activation of the 5-HT2A/C receptor, another subtype of 5-HT receptor present in the prefrontal cortex, increased NMDAR-mediated currents by increasing protein kinase C (PkC) and extracellular signal-regulated kinase (ERK) activity via the β-arrestin-dependent pathway (Yuen et al., 2008). Finally, 5-HT2A/C receptor activation attenuated the ability of 5HT1A receptors to suppress NMDAR currents, whereas blocking 5-HT2A/ C receptors unmasked the ability of these receptors to suppress NMDAR currents. Altogether, these studies suggest that 5-HT1A and 5-HT2A/C receptors converge on NMDAR signaling in a counteractive manner and provide new insight into the complex regulation of NMDAR-mediated synaptic transmission and plasticity by different 5-HT receptors (Yuen et al., 2008). The interaction between 5-HT receptors and NMDAR signaling seems to be a pervasive phenomenon across brain regions. In the nucleus accumbens of rats, activation of 5-HT1B receptors significantly decreased postsynaptic currents mediated by glutamate (Muramatsu et al., 1998). In synaptosomes derived from human neocortex, activation of 5-HT1D receptors on glutamate-releasing axon terminals decreased Ca2+-dependent, depolarization-evoked overflow of glutamate in this region (Muramatsu et al., 1998). In the rat entorhinal cortex, application of 5-HT depressed glutamate-evoked depolarization of layer II/III cells, which appears to be a postsynaptic phenomenon (Sizer et al., 1992). In the locus coeruleus of anesthetized rats, 5-HT selectively attenuated glutamate- and NMDA-evoked activation of NE-ergic neurons (Aston-Jones et al., 1991; Charlety et al., 1993). In fact, activation of 5HT2 receptors via systemic injection of their agonists influenced the locus coeruleus of rats and indirectly facilitated sensory inputs that act on NMDARs (Chiang and Aston-Jones, 1993). In the hippocampus of rats, 5-HT1B receptors are localized predominantly on terminals of CA1 neurons projecting to dorsal subiculum (Swanson et al., 1978). Activation of these receptors suppressed low frequency synaptic transmission in the rat subiculum (Boeijinga and Boddeke, 1996), suggesting that 5-HT1B receptors activation reduces the release of glutamate from fibers originating from CA1 pyramidal neurons (Boschert et al., 1994). Although there is some evidence that 5-HT1B receptors in the hippocampus contribute to serotonergic influence on learning (Buhot and Naili, 1995), the physiological consequences of hippocampal 5-HT1B receptor activation have not been elucidated fully (Fig. 2).

substantia nigra inhibited the local release of 5-HT, suggesting that 5HT neurons were regulated by glutamatergic neurons that innervate these regions. Later, it was shown that local injection of L-glutamic acid and NMDA into the caudate nucleus of the cat decreased 5-HT release from nerve terminals of 5-HT-ergic neurons of the dorsal raphe nucleus (Reisine et al., 1982). Conversely, NMDAR blockade increased 5-HTergic activity in the rat medial prefrontal cortex and dorsal hippocampus (Martin et al., 1998) and in neurons projecting from the rat dorsal raphe nucleus to the striatum (Lejeune et al., 1994)(Fig. 2). Loscher et al. later demonstrated that administration of MK-801 (dizocilpine), a non-competitive open channel blocker of NMDARs, increased 5-HT metabolism in several brain regions of rats, including the frontal and piriform cortices, nucleus accumbens, and striatum (Loscher et al., 1991). Others demonstrated that local perfusion and systemic administration of MK-801 increased extracellular 5-HT levels in the hippocampus (Whitton et al., 1992; Smolders et al., 2008), nucleus accumbens (Yan et al., 1997), and striatum (Lejeune et al., 1994; Whitton et al., 1992) of rats. Finally, it was shown that ineffective doses of NMDA antagonists (amantadine and budipine) combined with antidepressants (reboxetine, paroxetine and clomipramine) significantly increased cortical release of 5-HT in freely moving rats (Owen and Whitton, 2005). Interestingly, co-administration of amantadine or budipine with any of the three antidepressants resulted in two distinct differences. First, the time requisite for a significant increase in cortical 5-HT was reduced by > 50% (from 17 to 7 days). Second, the absolute magnitude of the increase in extracellular 5-HT was significantly greater till the end of the experiment (Owen and Whitton, 2005). Subsequent preclinical studies have demonstrated that NMDA exerted a dose-dependent effect that varied according to brain region. Infusion of low doses of NMDA (25 μM) into the rat raphe nuclei decreased extracellular 5-HT locally and increased extracellular 5-HT in the frontal cortex (Pallotta et al., 2001; Pallotta et al., 1998). Conversely, infusion of 100 μM NMDA into the rat raphe increased local 5HT and decreased cortical release of 5-HT (Pallotta et al., 1998; Smith and Whitton, 2000; Pallotta et al., 2001), effects that were more marked when the infusions were preceded by an acute injection of the SSRI clomipramine. Other preclinical studies demonstrated that repeated clomipramine treatment (15 days) dose-dependently increased basal extracellular 5-HT in both the raphe nucleus and frontal cortex and inhibited the effects of NMDA infusion (25 μM and 100 μM) on 5HT release in both regions (Pallotta et al., 2001). Tao and Auerbach (1996) reported that infusion of various concentrations of NMDA (30, 100, 300 μM) into the dorsal raphe nucleus of freely moving rats increased 5-HT levels locally and in the nucleus accumbens. Conversely, injection of NMDA into the nucleus accumbens, frontal cortex, and hippocampus decreased 5-HT levels in these regions (Tao and Auerbach, 1996). Extending these studies further, Fink et al. (1995) demonstrated that NMDA and L-glutamate elicit overflow of 5-HT in a concentrationdependent manner in rat cortical slices. Importantly, this effect was blocked by administration of several NMDAR antagonists including ifenprodil and eliprodil (Fink et al., 1995). Finally, Singewald et al. demonstrated that pain elicited by a tail pinch or superfusion of the locus coeruleus with NMDA agonists (50 μM) increased the rate of 5-HT release in freely moving rats, effects that were blocked by administration of NMDAR antagonists (Singewald et al., 1998). Together, these results suggest that 5-HT neurons of the raphe nuclei and locus coeruleus are modulated by excitatory amino acids acting on the NMDARs, particularly following stress. 3.2. Interactions between serotonin and NMDAR signaling While SSRIs rapidly inhibit 5-HT transporters within hours, their antidepressant effects emerge over the course of 2–3 weeks (Berman et al., 1997). Their delayed response has been linked to the dual function of 5-HT1A receptors implicated in the modulation of mood and 557

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Fig. 1. Schematic representation of proposed mechanism of serotonergic regulation of GluN2B subunit trafficking in neurons. Activation of 5-HT1A receptor inhibits PKA activity and, thereby, suppresses autophosphorylation and autonomous activity of calcium/calmodulin-dependent kinase II (CaMKII) via inhibition of the protein phosphatase 1 (PP1). Inhibition of PKA activity also decreases mitogenactivated protein kinase (MEK)/extracellular signalregulated kinases (ERK) activity. Decreased ERK or CaMKII activity results in decreased phosphorylation of microtubule-associated protein 2 (MAP2) and microtubule (MT) stability and a subsequent disruption of the MT/kinesin superfamily member 17 (KIF17)-mediated dendritic transport of GluN2Bcontaining vesicles, which leads to a significant reduction of the NMDAR-mediated currents. On the other hand, through the β-arrestin (β-Ar)-dependent pathway, activation of 5-HT2A/C increases activity of PkC and thereby activates ERK, leading to an increase in NMDAR-mediated currents. AC, adenylyl cyclase.

NE-ergic innervations of the hippocampus, a predominantly glutamatergic circuit (Storm-Mathisen, 1981) involved in emotion and cognition, arise from neurons of the locus coeruleus (Phillips et al., 2016). Emerging evidence suggests that stress related NE-ergic depletion in the hippocampus contributes to MD symptoms. Rodent studies suggest that NE levels are highest in the dentate gyrus of the hippocampus and lowest in NE-ergic fibers of CA1 (Hortnagl et al., 1991), suggesting that the CA1 region, an area prone to volumetric loss and structural abnormalities in persons with MDs (Rosoklija et al., 2000; Drevets et al., 2008), is vulnerable to stress-related NE-ergic depletion. Notwithstanding, the stimulating effect of NMDA or glutamate on NE release in the hippocampus was pharmacologically modulated with a variety of NMDAR antagonists (Andres et al., 1993; Malva et al., 1994; Jones et al., 1995; Clos et al., 1996; Mennini et al., 1997; Milusheva and Baranyi, 2003; Howells and Russell, 2008). Moreover, both acute and chronic administration of reboxetine (a selective NE uptake inhibitor) and fluoxetine (an SSRI) reduced NMDA/glycineevoked release of NE in rat hippocampal synaptosomes (Pittaluga et al., 2007). Moreover, the tricyclic antidepressant desipramine acutely inhibited NMDA-evoked NE release from rat hippocampal slices (Mayer et al., 2009). Consistently, infusion of the competitive NMDAR antagonist ( ± )-3(2-carboxypiperazin–4-yl)-propyl-1-phosphonic acid (CPP) by retrograde dialysis markedly inhibited stress-induced release of extracellular NE in the rat medial prefrontal cortex (Kawahara et al., 2000). Other studies have demonstrated that NMDAR activation either increased or stimulated the release of NE in cerebral cortex slices (Fink et al., 1989; Hoehn et al., 1990; Zhao et al., 1990) and synaptosomes (Fink et al., 1989, 1990; Wang et al., 1992), micro dialyzed rat prefrontal cortex (Lehmann et al., 1992; Tose et al., 2009), nerve terminals in olfactory bulb (Wang et al., 1992), superfused slices of mediobasal hypothalamus (Navarro et al., 1994) and rat hypothalamic slices and nerve terminals (Blandina et al., 1992; Goldfarb et al., 1993; Navarro et al., 1995), rat hypothalamic paraventricular nucleus (Okada and Yamaguchi, 2010), rat laterodorsal tegmental nucleus in the pons (Kodama and Koyama, 2006) and rat spinal cord slices (Klarica et al.,

3.3. Noradrenergic transmission Several studies have implicated noradrenergic and glutamatergic dysfunction in MD pathobiology. Clinical studies from the mid-1950s demonstrated that administration of tetrabenazine (causing depletion of MAs) and reserpine (which blocks vesicular monoamine transporter) induced depressive symptoms in persons with hypertension (Schildkraut, 1995). Later studies implicated glutamatergic inputs to abnormal locus coeruleus activity in persons with MDs (Miguel-Hidalgo et al., 2010; Chandley et al., 2013; Murase et al., 1992). Post mortem studies demonstrated that locus coeruleus neurons of suicide completers contained increased levels of tyrosine hydroxylase protein (Ordway et al., 1994), i.e. an enzyme necessary for NE synthesis and linked to high stress levels. Moreover, it was shown that increased agonist binding to α2- adrenergic receptors (ARs) occurred in the hypothalamus (Meana et al., 1992), locus coeruleus (Ordway et al., 2003), frontal cortex, and the hippocampus (Gonzalez et al., 1994) of persons with MDs. The increased binding is important because presynaptic αARs are responsible for the inhibition of NE synthesis and release (Knaus et al., 2007), whereas α-ARs on non-NE-ergic terminals are responsible for the regulation of glutamate release (Shields et al., 2009). Finally, it has been shown that infusion of an NMDA receptor antagonist (CPP) suppressed the stimulation of NE during handling stress (Kawahara et al., 2000), findings that suggest a role for NMDARs receptors in the suppression of sensory responsiveness of locus coeruleus neurons (Murase et al., 1992). Numerous lines of evidence suggest that activation of NMDARs regulate the release of NE, an important finding given that NE levels are associated with MD symptoms in humans (Gu et al., 2016; Kurita, 2016). Preliminary work in the late 1980s and early 1990s reported that activation of NMDARs increased NE release in rodent hippocampal slices (Jones et al., 1987; Pittaluga et al., 1993) and synaptosomes (Malva et al., 1994; Clos et al., 1996; Pittaluga and Raiteri, 1992; Wang et al., 1992). Further investigation showed that NMDARs were found on NE-ergic terminals in the hippocampus where they mediate the enhancement of NE release (Pittaluga and Raiteri, 1990). 558

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Fig. 2. Schematic representation of intracellular interaction between monoaminergic and NMDA receptor signaling. Cell-surface receptors transduce extracellular signals such as neurotransmitters and neuropeptides into the interior of the cell. 5-HT1A receptor activation in hippocampus counteracts NMDAR-evoked accumulation of cGMP and downregulates nNOS expression. 5-HT regulates stress-related behaviors via 5-HT1A receptor/nNOS/cAMP response element-binding protein (CREB) pathway in the hippocampus. Activation of α2-ARs decreases NOS activation/cGMP formation in several brain regions such as hippocampus, cortex, cerebellum, locus coeruleus, and caudate nucleus. However, activation of either α1- or βARs stimulates cGMP accumulation in a number of brain regions. Serotonergic and ARs are G-protein-coupled receptors (GPCRs) that modulate adenylyl cyclase (AC) activation and, thereby, cAMP formation. cAMP activates PKA and, thereby, directly or indirectly induces the transcription of several important factors such as CREB, c-Fos, c-Jun, Jun-D, and Δfos-B.

dependent on the density and functional integrity of pre- and postsynaptic adrenoceptors (ARs). There are two main groups of αARs (the α1 Gq coupled receptor and the α2 Gi coupled receptor) and three subgroups of β-ARs (β1, β2 and β3, all of which are Gs and adenylyl cyclase, although, β2 also couples to Gi). NE release from NE-ergic nerve terminals is controlled by presynaptic α2-ARs (Starke et al., 1989). Moreover, heteroreceptors are located on the presynaptic membranes and are acted upon by other neurotransmitters that are released from adjacent terminals or by co-localized transmitters. Presynaptic heteroreceptors inhibit or facilitate the release of neurotransmitters. Studies in the early 1980s by Dolphin revealed that stimulation of β2-ARs facilitated the release of glutamate in slices of rat cerebellum, an effect potentially mediated by adenylate cyclase activation (Dolphin, 1982). Also, it was shown that phentolamine (α-AR antagonist) and NE increased glutamate release, whereas sole administration of phentolamine had no effect on glutamate release, suggesting that β-AR stimulation of glutamate release by NE may occur when α-ARs are blocked (Dolphin, 1982). Both α- and β-ARs are known to be present in the terminal fibers of

1996; Sundstrom et al., 1998). NMDAR antagonists also inhibited nicotine-induced release of NE in NE-ergic nerves in the rat paraventricular nucleus and amygdala that project from the brainstem and nucleus tractus solitarius (Zhao et al., 2007). Systemic and local administration of MK-801 increased NE in the nucleus accumbens (Yan et al., 1997). Local application of 0.5 mM NMDA into the supraoptic nucleus decreased NE content in this region whereas NMDAR antagonists have the opposite effects (Liu et al., 2001). Ketamine markedly increased NE release from the rat medial prefrontal cortex (Kubota et al., 1999). Infusions of NMDA and kainate into the locus coeruleus markedly increased extracellular NE in the prefrontal cortex (Van Gaalen et al., 1997). Altogether, these studies further support the interaction between the NE-ergic and glutamatergic systems, particularly in locus coeruleus projection areas.

Interactions between norepinephrine and NMDAR signaling Besides the amount of NE released into the synaptic cleft and the rate of removal of the neurotransmitter from the synaptic cleft, the physiological consequences of sympathetic nerve firing is also 559

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3.4. Neurotrophic factors

noradrenergic neurons that project to the anterior olfactory nucleus, olfactory tubercle, and piriform cortex. Exploring the effects of excitatory transmission in rat olfactory cortex slices, Collins et al. observed that bath application of low concentrations of NE (0.2–5 μM) facilitated transmission, whereas higher doses (10–250 μM) depressed it (Collins et al., 1984). Lynch and Bliss showed that NE, clonidine (an α2-AR agonist), and isoprenaline (a β-AR agonist), but not phenylephrine (an α1-AR agonist), increased glutamate release in slices prepared from the dentate gyrus of the rat hippocampus. This effect was prevented by administration of propranolol (a β-AR antagonist), but not by yohimbine or phentolamine (α-AR antagonists) (Lynch and Bliss, 1986). Consequently, the underlying action of NE is to potentiate the release of excitatory neurotransmitters and NE modulates glutamate release in the dentate gyrus by acting on presynaptic βARs. Modulation of glutamate release by NE plays an important physiological role in the induction of LTP in the dentate gyrus, which is dependent upon the sustained increase in glutamate release (Dolphin, 1982; Bliss et al., 1983b). Depletion of NE impairs LTP in the dentate gyrus (Bliss et al., 1983a) and, thereby, leads to memory failure, a phenomenon that is mitigated by the restoration of NE levels (Salehi et al., 2009). Importantly, preclinical evidence suggests that α2-AR activation inhibits glutamate overflow in hippocampal synaptosomes (Kamisaki et al., 1992). Moreover, presynaptic α2-AR activation inhibits the release of glutamate in striatal and cortical slices (Crowder and Bradford, 1987) along with synaptosomes from posterior cortex, anterior cortex, thalamus, hypothalamus, spinal cord (Kamisaki et al., 1991, 1992, 1993); and the bed of the nucleus stria terminalis (Forray et al., 1999). Together, these findings suggest that chronic stimulation of presynaptic ARs (which inhibits the release of NE) inhibits glutamate release in several brain regions and, thereby, impair cellular function including LTP. Conversely, activation of presynaptic α1-ARs in other brain regions such as the paraventricular nucleus increased the excitability of presynaptic neurons through augmentation of glutamatergic tone and attenuation of GABAergic inputs (Chen et al., 2006a). Tingley and Arneric showed that clonidine enhanced the basal release of GABA, aspartate, and glutamate in the medulla oblongata of rats with spontaneous hypertension via mechanisms that involved activation of α2-ARs (Tingley and Arneric, 1990). Other evidence suggested that the NE-ergic system modulates the reuptake of glutamate in a number of brain regions. Using cerebral cortex astrocytes from neonatal rats, Hansson et al. showed that α1-ARs regulated the active uptake of glutamate and that low concentrations of the β-AR agonist isoproterenol inhibited glutamate uptake, suggesting that astrocyte ARs modulate neurotransmitter-induced neuronal excitability (Hansson and Ronnback, 1989). Several other preclinical studies have demonstrated reciprocal interactions between NE-ergic transmission and NMDARs across brain regions, including the hippocampus and brainstem (Bickler and Hansen, 1996; Ohno et al., 1996; Bertolino et al., 1997; Harkin et al., 2001), prefrontal cortex (Law-Tho et al., 1993; Van Gaalen et al., 1997; van Stegeren, 2008), cortex (Starke, 1977; Fink et al., 1989; Fink and Gothert, 1992, 1993; Kobayashi et al., 2009), and hypothalamus (Okada and Yamaguchi, 2010). Altogether, these studies suggest that NE-ergic system function reciprocally interacts with NMDARs via several receptor subtypes, and results in variable effects in a dose and region-dependent manner. Complicating analysis of these modulatory effects are interactions with other neurotransmitters, warranting further study of these specific mechanisms. Moreover, the delayed treatment effects of monotherapies versus the rapid effects of NMDAR antagonists in MDs suggest that they are involvement in downstream mechanisms. Indeed, recent evidence has demonstrated that NMDAR activity effectuates changes in neuroplasticity, synaptic protein expression, and dendritic spine morphogenesis (Duman and Aghajanian, 2012; Hoeffer and Klann, 2010), changes that appear vitally important to antidepressant action. Factors that affect these mechanisms include neurotrophic levels and inflammation and, accordingly, are reviewed below in brief.

Neurotrophic factors (NTs) are members of a small family of proteins that support growth, survival, and physiological function of neurons and glia. Members of this family include nerve growth factor, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 and 4. Initially, NTs are synthesized as proneurotrophins that mediate their biological actions through binding to low affinity p75 neurotrophin receptors (P75NTR). Following processing, proneurotrophins are converted to mature NTs and then bind with high affinity to various subtypes of tropomyosin receptor kinase (Trk) receptors (A, B, C). For instance, mature BDNF primarily binds to TrkB receptors (Villanueva, 2013). The functional importance of differential binding to either p75NTR or Trk receptors is underscored by their opposing effects: mature neurotrophin binding to Trk receptors promotes cell survival (Lee et al., 2001a), LTP, and plasticity (Kang and Schuman, 1996; Messaoudi et al., 2002), whereas proneurotrophin binding to p75NTR induces neuronal apoptosis (Lee et al., 2001b; Lu et al., 2005). Changes in the expression and function of NTs have been implicated in the atrophy, synaptic loss, and dysfunction of MD-related circuits (Duman, 2014; Krishnan and Nestler, 2008; Poletti et al., 2016; Savitz and Drevets, 2009), a phenomenon linked to altered NMDAR signaling (Autry et al., 2011; Garcia et al., 2008). This is not surprising given NTs vital role in promoting synaptic plasticity and remodeling, the induction of LTP, modulation of gene expression, and resilience to neuronal insults (Duman, 2014; Krishnan and Nestler, 2008; Savitz and Drevets, 2009; Teixeira et al., 2010). Of the NTs, BDNF has emerged as a robust survival factor that is strongly implicated in MD pathobiology (Table 1). A number of recent preclinical and clinical studies have suggested an association between BDNF-TrkB signaling and depressive disorders (Mitre et al., 2017). For instance, BDNF infusion in the midbrain leads to antidepressant effects in mice (Siuciak et al., 1997). Furthermore, performing the forced swim test in animal models of depression is associated with reduced BDNF gene expression in the hippocampus (Russo-Neustadt et al., 1999). Accordingly, both BDNF-knockout and TrkB mutant mice are resistant to antidepressant treatments (Saarelainen et al., 2003). A number of clinical studies have documented reduction in BDNF in the hippocampus and prefrontal cortex of suicide completers (Dwivedi et al., 2003; Karege et al., 2005). Peripheral reductions in mature BDNF in serum and plasma have been reported in persons with depression (Birkenhager et al., 2012; Karege et al., 2002; Lee et al., 2007). In addition to altered levels of BDNF, polymorphisms in BDNF gene (Val66Met) have been associated with depression-related phenotypes (Cardoner et al., 2013; Kang et al., 2015). Similarly, peripheral reduction in mature BDNF in serum and plasma has been reported during the manic and depressive phases of BP (Cunha et al., 2006; Fernandes et al., 2015; Lin et al., 2016; Munkholm et al., 2016). Notwithstanding, one study demonstrated that intravenous ketamine administration increased plasma BDNF (Duncan et al., 2013). Another study demonstrated that serum BDNF is significantly reduced at 1 week in bipolardepressed ketamine non-responders (Rybakowski et al., 2013). Some evidence suggests that increased production of BDNF occurred during the course of BP disease so as to repair neural damage, particularly given that a longer disease course was associated with higher BDNF levels in BP (Munkholm et al., 2016), effects that were abrogated by neuroinflammatory processes (Poletti et al., 2016). Preclinical and clinical studies suggest that the BDNF Val/Met polymorphism attenuates the antidepressant response to ketamine infusion (Laje et al., 2012; Liu et al., 2012), suggesting that the administration of BDNF-enhancing techniques (e.g., exercise and transcranial stimulation) prior to ketamine administration may improve the overall response (Laje et al., 2012). A recent meta-analysis reported significantly lower serum levels of BDNF in antidepressant-free patients with MDD as compared to healthy individuals (Molendijk et al., 2014). As mentioned above, BDNF is 560

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Table 1 Mood disorders and trophic factor signaling. Study

Experimental treatment

Outcome Assessment

Results

Cheng and Mattson (1994)

Rat hippocampal, septal, and cortical cultures experiencing glucose deprivation and depleted of glial cells were exposed to BDNF and NT-3. Sprague-Dawley were daily administered electroconvulsive seizures and intraperitoneal injections of either tranylcypromine, imipramine, desipramine, sertraline, fluoxetine, haloperidol, cocaine, rolipram, or papaverine. Centrally-administered midbrain BDNF infusion (12–24 μg/day for 7 days) to Sprague-Dawley rats.

Quantification of neuronal survival and measurement of intracellular Ca2+.

Pretreatment with BDNF and NT-3 attenuated glucose-deprivation induced neuronal death by stabilizing Ca2+ homeostasis. BDNF and TrkB mRNA levels were increased in the dentate gyrus following administration of fluoxetine and tranylcypromine (a monoamine oxidase inhibitor).

Learned helplessness following inescapable shock and forced swim.

Brandoli et al. (1998)

Exposure of cerebellar granule cell cultures taken from Sprague-Dawley pups to BDNF and FGF2.

Measurement of mRNA and/or protein for NR1, NR2A, NR2B, and NR2C.

Russo-Neustadt et al. (1999)

Intraperitoneal injection of imipramine (15 mg/kg) or a monoamine oxidase inhibitor (tranylcypromine, 7.5 mg/kg) to Sprague-Dawley rats and engagement in voluntary physical activity on running wheels. Intraperitoneal injection of imipramine (30 mg/kg) and fluoxetine (20 mg/kg) in tg mice (TrkB.T1) with reduced TrkB activation and heterozygous BDNF null mice. Sprague-Dawley rats received intracerebroventricular infusion of BDNF and IGF-1. Central infusion of BDNF into hippocampus of Sprague-Dawley rats.

BDNF mRNA in the hippocampus.

Nibuya et al. (1996)

Siuciak et al. (1997)

Saarelainen et al. (2003)

Hoshaw et al. (2005) Scharfman et al. (2005)

BDNF and TrkB mRNA measurement.

Forced swim test.

Forced swim test. BrdU/NeuN double-labeling of hippocampal samples.

Jiang et al. (2005).

Exposure of hippocampal cultures taken from Sprague-Dawley embryos to 50 μM of NMDA.

BDNF protein and mRNA measurements.

Chen et al. (2006a).

BDNF (Met/Met) mice subjected to stress and then administered fluoxetine.

Open-field and elevated plus maze tests.

Berton et al. (2006).

Exposure of virally-mediated, mesolimbic dopamine pathway-specific BDNF knock-down mice to social defeat.

DNA microarray and BDNF levels in nucleus accumbens.

Monteggia et al. (2007)

Exposure of BDNF conditional knockout mice to forced swim and then administration of desipramine

Forced swim test, open field, sucrose preference test, and elevated plus maze.

Nair et al. (2007)

Acute and chronic immobilization stress to SpragueDawley adult rats and maternal separation stress in the pups.

Novelty suppressed feeding test, quantification of BDNF exon-specific transcripts, BrdU-positive cells in hippocampus.

Garcia et al. (2008)

Wistar rats were administered ketamine and imipramine and then subjected to forced swim and open-field tests. Sprague-Dawley rats were injected twice daily with lamotrigine and subjected to forced swim and inescapable foot shock.

Forced swim and open-field tests and BDNF protein measurements.

Li et al. (2010a)

Schmidt and Duman (2010)

Peripheral BDNF infusion to C57Bl/6 and BALB/c mice followed with forced swim, chronic unpredictable stress, novelty induced feeding, and elevated plus maze.

Forced swim test, inescapable foot shock, and measurement of BDNF protein in the hippocampus.

forced swim, chronic unpredictable stress, novelty induced feeding, and elevated plus maze, striatal expression of BDNF, BrdUlabeling of hippocampal and prefrontal cortex.

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Multiple administration of BDNF mitigated depressive-like symptoms (i.e., decreased escapes and increased latency to escape) and forced swim test. Exposure of cultures to BDNF and FGF2 reduced NR2A subunit protein levels, NR2A and NR2C subunit mRNA levels, and mitigated NMDA-mediated Ca2+ response following stimulation. Combined antidepressant treatment with physical activity had an additive, potentiating effect on BDNF mRNA expression in hippocampus. Rodents with endogenous BDNF deficits were resistant to effects of antidepressant treatment (no decrease in immobility time). Both BDNF and IGF-1 reduced depressive symptoms. BDNF infusion increased neurogenesis in the dentate gyrus both ipsilateral and contralateral to the infusion site. NMDA evoked the release of BDNF and accumulation of BDNF in the medium effectuated an increase in the phosphorylation of TrkB receptors and BDNF mRNA, effects that were attenuated by pre-incubation with a BDNF-blocking antibody and TrkB-IgG BDNF (Met/Met) demonstrated increased anxiety-like behavior that was not normalized by antidepressants. Ventral tegmental area deletion of BDNF and administration of fluoxetine attenuate social aversion after defeat stress and reverses gene expression profiles following stress (mitigates upregulation of 309 genes in nucleus accumbens and down regulation of 17 genes. Female BDNF knockout mice showed greater depressive-like behaviors than male mice. The Loss of BDNF attenuated antidepressant effects of desipramine. Early life stress of maternal separation increased proliferation of hippocampal progenitor cells during early post-natal life and resulted in a time-dependent differential upregulation of BDNF transcripts restricted to early postnatal life. In adulthood, distinct stressors regulated BDNF in a specific manner. Acute stress decreased BDNF mRNA of all splice variants whereas chronic stress increased BDNF I/II and decreased III/IV variants. Ketamine and imipramine mitigated depressive behaviors (immobility). Moreover, ketamine increased BDNF protein levels. Lamotrigine decreased depressive and learned helplessness behaviors (decreased escape failures and reduced immobility in forced swim) and increased BDNF expression in frontal cortex and the hippocampus. Peripheral BDNF administration decreased depressive and anxiety behaviors (forced swim test, attenuated effects of chronic stress on sucrose consumption, decreased latency on novelty induced feeding, and increased); partially mitigated effects of chronic stress. (continued on next page)

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Table 1 (continued) Study

Experimental treatment

Outcome Assessment

Taliaz et al. (2011)

Exposure of Sprague-Dawley animals to chronic mild stress after lentiviral vectors were used to induce BDNF overexpression or knockdown in the hippocampus.

Plasma corticosterone, hippocampal BDNF, sucrose preference test, novelty induced behavior, home-cage exploration, forced swim.

Autry et al. (2011)

Intraperitoneal injection of ketamine, MK-801, or CPP to BDNF knock-out mice subjected to forced swim.

Liu et al. (2012)

Whole-cell recordings of pyramidal cells in brain slices taken from Val/Val, Val/Met, and Met/Met mice that received low doses of ketamine.

Forced swim, sucrose consumption test, elevated plus maze, novelty suppressed feeding, context and cued fear conditioning, learned helplessness, chronic mild stress. Whole-cell recordings of layer 5 of medial prefrontal cortex neurons in brain slices.

Lakshminarasimhan and Chattarji (2012)

Acute and chronic immobilization stress to Wistar rats.

Corticosterone and BDNF measurements.

Mao et al. (2014)

Piperine and imipramine administration to SpragueDawley rats exposed to chronic unpredictable stress.

Forced swim test, sucrose consumption, measurement of BDNF and serotonin levels in the hippocampus and frontal cortex.

Zhang et al. (2015)

Exposure of C57BL/6 mice to social defeat stress and then administered single dose of ketamine.

Tail suspension and forced swim test.

Results No effects on cell proliferation, in the hippocampus and prefrontal cortex and increased BDNF levels in the hippocampus. Reduction in hippocampal BDNF expression in young rats induced prolonged elevation of corticosterone secretion along with improved mobility in forced swim test and no significant effects on sucrose consumption and distance travelled. Rapid synthesis of BDNF after ketamine, MK801, and CPP. Moreover, reduced eEF2 phosphorylation and increased BDNF translation. Val/Met and Met/Met mice exhibited atrophy of distal apical dendrites and decrements in excitatory post-synaptic currents. Effects of ketamine were markedly reduced in Met/Met mice. Chronic stress upregulates corticosterone, decreases BDNF expression in CA3, and upregulates BDNF in basal lateral amygdala. Acute stress does not change BDNF in CA3, but does upregulate BDNF expression in basal lateral amygdala. Chronic piperine and imipramine administration mitigated deficits in BDNF and depressive-like behavior (attenuated stress induced decrements in sucrose consumption and attenuated immobility in forced swim test). Antidepressant effects of ketamine was present 7 days after infusion; ketamine attenuated decrements in BDNF and PSD95 in prefrontal cortex, dentate gyrus, and CA3 region of the hippocampus. In addition, ketamine significantly increased GluA1 in the prefrontal cortex and the dentate gyrus).

ventral tegmental area and nucleus accumbens was positively associated with plasticity-induced aversive learning (Goggi et al., 2003; Grimm et al., 2003). The nucleus accumbens in the basal forebrain is a major component of the ventral striatum and a brain circuit believed to regulate pleasure and happiness (Loonen and Ivanova, 2016). It has been shown that BDNF potentiates dopamine release in this region through activation of TrkB receptors on dopaminergic nerve terminals (Goggi et al., 2003; Wook Koo et al., 2016) and, in turn, regulated nucleus accumbens function by acting on TrkB receptors (Grimm et al., 2003; Guillin et al., 2001; Horger et al., 1999). Interestingly, ketamine did not appear to increase BDNF in the nucleus accumbens (Autry et al., 2011; Zhang et al., 2015). Others demonstrated that chronic stress increased BDNF levels in the amygdala (Lakshminarasimhan and Chattarji, 2012). Together, these studies suggest that the anti- or prodepressive effects of BDNF depend upon the brain region affected and offer evidence that selectively targeting BDNF levels in key brain regions may benefit patients affected by MDs. Another method by which altered BDNF and glutamatergic function may modulate MD pathophysiology is by altering the rate of neurogenesis in the hippocampus (Paul and Skolnick, 2003; Rubio-Casillas and Fernandez-Guasti, 2016). A growing body of evidence suggests that MDs are associated with reduced hippocampal neurogenesis (Alonso et al., 2004; Bjornebekk et al., 2006; Lucassen et al., 2006; Mineur et al., 2007; Vega-Rivera et al., 2014) and loss of glial elements (Banasr and Duman, 2008; Pittenger and Duman, 2008), but that central (Scharfman et al., 2005) and peripheral administration of BDNF in the hippocampus increases the rate of neurogenesis (Schmidt and Duman, 2010). Notably, glutamate appears essential for the process of neurogenesis. Physiological excitation of NMDARs promoted BDNF-induced

produced by proteolytic cleavage of pro-BDNF. Importantly, both molecules have been detected in human plasma samples (Yoshimura et al., 2016). Persons with MDD exhibited a higher ratio of mature BDNF to pro-BDNF in their blood samples in comparison to those with BP, but this ratio was restored following response to antidepressants, suggesting that mature- to pro-BDNF ratio in the periphery may serve as a diagnostic biomarker for depressive episodes in persons with BP (Zhao et al., 2016). Preclinical studies further linked decrements in BDNF in key brain regions (e.g., hippocampal CA3 region and forebrain) to depressive-like symptoms along with altered BDNF synthesis and TrkB signaling (Lakshminarasimhan and Chattarji, 2012; Li et al., 2013; Li et al., 2011; Mao et al., 2014; Nair et al., 2007; Zhang et al., 2015; Zhang et al., 2014), effects that can be mitigated with increased BDNF levels in the hippocampus (Hoshaw et al., 2005; Shirayama et al., 2002; Siuciak et al., 1997; Ye et al., 2011; Taliaz et al., 2011). Notably, the effects of antidepressants (i.e., desipramine, fluoxetine, ketamine) can be blocked in mice by deleting the BDNF gene in forebrain regions (Monteggia et al., 2007; Chen et al., 2006b; Liu et al., 2012), suggesting that decrements in BDNF play a central role in antidepressant effects in this region. Further supporting the importance of BDNF signaling are recent findings from Zhang et al. (2015) wherein ketamine demonstrated more protracted antidepressant effects than the TrkB agonist 7,8-dihydroxyflavone (DHF) following social-defeat stress, suggesting that ketamine’s mechanism of action may involve long-lasting activation of BDNF-TrkB signaling in certain brain regions (e.g., prefrontal cortex and CA3 region) (Zhang et al., 2015). Conversely, removing the BDNF gene from the mesolimbic dopamine pathway reduced social aversion following chronic social defeat (Berton et al., 2006), suggesting that BDNF in the 562

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following response to antidepressants (Myint et al., 2005); (v) inflammatory ratios are higher in persons who are manic than in healthy controls (Kim et al., 2007); (vi) anti-inflammatory drugs have antidepressant effects (Krishnan et al., 2007; Menter et al., 2010; Soczynska et al., 2009) and some non-steroidal anti-inflammatory drugs (e.g., naproxen) mitigate depressive and manic symptoms (Abbott et al., 2015; Fond et al., 2014; Kohler et al., 2014; Tyring et al., 2006); (vii) some classes of antidepressants and mood stabilizers decrease the production of pro-inflammatory cytokines (e.g., INF-γ and TNF-α) and increase anti-inflammatory cytokines in both clinical and preclinical studies (e.g., IL-10) (Elgarf et al., 2014; Kenis and Maes, 2002; Kim et al., 2007; Knijff et al., 2007; Miller et al., 2009; Ohgi et al., 2013; Tuglu et al., 2003); viii) there are region-specific alterations to the ratio of AMPA receptors (AMPARs) to NMDAR subunits in post mortem samples of persons with MDD and BP (Beneyto et al., 2007; Beneyto and Meador-Woodruff, 2008; Feyissa et al., 2009; Karolewicz et al., 2005; Karolewicz et al., 2009); ix) decreased glial numbers and density in multiple brain regions (e.g., prefrontal, orbitofrontal, anterior, subgenual frontal, entorhinal, and amygdala) occur in persons with MDs (Bowley et al., 2002; Cotter et al., 2001; Gittins and Harrison, 2011; Ongur et al., 1998; Rajkowska et al., 1999); x) there is a positive association between inflammation, increased glutamate, and glial dysfunction in the basal ganglia of medication-free persons with MDD (Haroon et al., 2016); xi) the blocking of excitatory amino-acid transporters on glia (which clear glutamate from the synaptic cleft) in the medial prefrontal induces depressive-like behaviors in rodents (Banasr and Duman, 2008; Sanacora and Banasr, 2013); and xii) the decreased expression of excitatory amino-acid transporters on glia in rodents is associated with learned helplessness behaviors (Zink et al., 2010). The implications of chronic inflammatory processes are problematic given their ability to dysregulate neurotransmission and trophic factor signaling as well as effectuate decrements in neurogenesis and neuroplasticity (Dantzer et al., 2008; Gold et al., 2015; Khairova et al., 2009; McNally et al., 2008; Miller et al., 2009; Skolnick et al., 2009). Moreover, chronic inflammatory processes can contribute to glutamatemediated excitotoxicity (Gold et al., 2015; Khairova et al., 2009) and loss and dysfunction of glial cells in persons with MDDs (Altshuler et al., 2010; Johnston-Wilson et al., 2000; Muller et al., 2001; Ongur et al., 1998; Si et al., 2004; Webster et al., 2001). That is, inflammation may increase the release and spillover of glutamate into the extrasynaptic cleft by inhibiting the ability of glial transporters to clear glutamate (McCullumsmith and Sanacora, 2015; McNally et al., 2008). In turn, the excessive glutamate can activate extrasynaptic NMDAR activity and effectuate the retraction of dendritic spines, loss of synapses, and neuronal loss (Hardingham and Bading, 2010; Marsden, 2011). To combat immune-mediated neuronal vulnerability, NMDA antagonists like ketamine and memantine have been deployed. Accordingly, ketamine has been shown to mitigate depressive-like behavior in rodents (Walker et al., 2013) along with the expression of proinflammatory cytokines (e.g., TNF-α, IL-6, inducible nitric oxide synthase, nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB], and activator protein [AP]-1) (Helmer et al., 2003; Taniguchi et al., 2003a; Taniguchi et al., 2003b) in immune-stimulated rodents. In human whole blood, it has been shown that ketamine reduces cytokine production (e.g., TNF, IL-6, and IL-8) following inoculation with gram positive enterotoxin (Kawasaki et al., 2001). Currently it is unknown if the anti-inflammatory effect of ketamine is derived from antidepressant- or neuroprotectant-related mechanisms, but some preclinical evidence in rats suggest that ketamine abrogates neuronal death caused by excitotoxicity (Anand et al., 2007). Together, the aforementioned evidence suggests a point of convergence between inflammatory mediators, glutamatergic/NMDAR signaling, and the pathophysiology of MDs. Knowledge of this emphasizes the need to better discern how NMDAR modulators may be used to normalize inflammation, glial function, trophic factor signaling, synaptic integrity, and mood regulation. Also, imperative to future work

neuroprotection against excitotoxicity (Jiang et al., 2005), but persistent NMDAR activation blocked BDNF signaling in cell cultures (Soriano et al., 2006). Parallel clinical and preclinical studies have shown that chronic administration of antidepressants, mood stabilizers, and NMDAR antagonists (e.g., fluoxetine, lithium, valproic acid, lamotrigine, and ketamine) mitigated decrements in BDNF in MDs (Chen et al., 2015; Fukumoto et al., 2001; Gama et al., 2007; Garcia et al., 2008; Hashimoto et al., 2002; Ikenouchi-Sugita et al., 2009; Li et al., 2010a; Nibuya et al., 1996; Polyakova et al., 2015; Reus et al., 2015). A number of recent interventional studies suggests that the possible efficacy of deep brain stimulation (DBS) in treatment resistant depression involves modulation of BDNF and glutamatergic function. DBS of different brain regions (nucleus accumbens, ventral striatum/ventral capsule, subgenual cingulate cortex, lateral habenula, inferior thalamic nucleus, and medial forebrain bundle) is known to mitigate depressive symptoms in 40–70% of treatment-refractory patients (Morishita et al., 2014), although the effects can take weeks to months to reify, suggesting plasticity-induced effects (Kuhn et al., 2010; McCracken and Grace, 2009). Parallel work has shown that DBS increases BDNF levels in the rat brain (Friedman et al., 2009) and in human blood (Hoyer et al., 2012). Moreover, high-frequency stimulation of glutamatergic synapses in the hippocampus effectuates release of BDNF from dendrites (Hartmann et al., 2001), whereas prolonged stimulation of glutamatergic synapses effectuates axonal release (Matsuda et al., 2009), suggesting that stimulation-induced increases in BDNF may occur in vivo (Sakata and Duke, 2014) and contribute to the possible efficacy of DBS. Not surprisingly, tight regulation of BDNF-NMDA interactions is requisite to prevent excitotoxicity. It has been shown that BDNF prevents neuronal death and glial activation after global ischemia in the rat (Kiprianova et al., 1999) and modulates NMDAR-mediated glutamate toxicity in primary culture (Cheng and Mattson, 1994; Lindholm et al., 1993). These protective effects may involve a dampening of NMDAR function, a notion supported by evidence showing that incubation of primary neuron cell cultures with BDNF decreases mRNA levels encoding ε subunits of NMDA receptors (Brandoli et al., 1998). Also implicated in ketamine’s rapid antidepressant effects is the deactivation of eukaryotic elongation factor 2 kinase (eEF2), which results in reduced eEF2 phosphorylation and, in turn, blocking effects of BDNF translation (Autry et al., 2011; Heise et al., 2014; Nosyreva et al., 2013). Altogether, the aforementioned suggests that targeting BDNF and its TrkB receptor represent another therapeutic strategy for MDs (Castren, 2014; Duman and Monteggia, 2006; Hashimoto, 2010, 2013; Hashimoto et al., 2004; Homberg et al., 2014; Nestler et al., 2002). 3.5. Inflammatory processes Excessive inflammatory activation and glutamatergic abnormalities are implicated in MD pathophysiology (Dantzer et al., 2008; Dowlati et al., 2010; Haroon and Miller, 2017; Howren et al., 2009; Sanacora and Banasr, 2013; Sanacora et al., 2012). Bolstering this notion are several key findings showing that: (i) chronic inflammatory disorders (e.g., cardiovascular disease, type-2 diabetes, rheumatoid arthritis, Crohn’s disease, cancer, human immunodeficiency virus, and multiple sclerosis) are associated with an increased prevalence of MDD (Benton et al., 2007; Elenkov, 2008; Godin et al., 2014; Perugi et al., 2015; Rotella and Mannucci, 2013; Vancampfort et al., 2013); (ii) persons treated with recombinant human cytokines (e.g., interleukin (IL)-2 and interferon (IFN)-α) often develop MDD (Evon et al., 2014; Mahajan et al., 2014; Medeiros et al., 2014; Raison et al., 2006); (iii) a subgroup of patients with depression and mania exhibit elevated plasma levels of proinflammatory cytokines (e.g., IL-1, IL-2, IL-6, tumor necrosis factor (TNF), and C-reactive protein) (Bremmer et al., 2008; Hiles et al., 2012; Modabbernia et al., 2013; Rosenblat and McIntyre, 2015; Soczynska et al., 2009; Thomas et al., 2005); (iv) persons with depression exhibit a higher ratio of IFN-γ to IL-4 prior to treatment, a trend that normalizes 563

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2010b), whereas inhibition of mTOR using rapamycin blocks the antidepressant effects of ketamine (Li et al., 2010b). Finally, ketamine induces synaptogenesis and glutamate transmission, effectuating increased levels of BDNF and TrkB signaling (Abelaira et al., 2014). Together, these studies suggest utility for ketamine to mitigate MD symptoms. However, the efficacy of a single infusion may be insufficient to produce long-term clinical improvement in the MD population, warranting increased attention to the issue of repeated infusions (Murrough et al., 2013; Rasmussen et al., 2013; Shiroma et al., 2014). Also, future studies need to assess long-term side effects and benefits and cost effectiveness of both single and repeated infusions. More work is needed to investigate optimal dosing and alternative methods of drug delivery (e.g., intranasal, intramuscular, and sublingual), particularly given the fact that parenteral infusions are resource-intensive. Notwithstanding, significant clinical concerns with the use of ketamine as an antidepressant pertain to its psychotomimetic effects, abuse liability, and possible neurotoxicity with chronic administration (Abdallah et al., 2015).

is a critical consideration of how dosage of NMDAR antagonists may contribute to neuroprotection according to the stage of disease and in the context of inflammatory complexity. 4. Translational aspects of NMDARs antagonists in mood disorders Several preclinical studies have demonstrated rapid and robust effects of NMDAR antagonists on depressive-like symptoms in models of MDs (Trullas and Skolnick, 1990) and, in turn, sparked a number of clinical trials using NMDAR modulators. Here we highlight candidates targeting the glutamatergic system that have demonstrated clinical efficacy in the treatment of MDs as reported in the clinical trials registry with clinicaltrials.gov. Notably, much of this evidence suggests that rapid antidepressant effects are achievable in humans (Machado-Vieira et al., 2008). 4.1. Ketamine Ketamine is a voltage dependent NMDA antagonist that is used widely as a general anesthetic in both animals and humans. Ketamine has a high affinity for NMDARs, with slow open-channel blocking/unblocking kinetics (Machado-Vieira et al., 2009). Moreover, ketamine directly affects voltage-operated calcium channels and receptors for opioids, AMPAs, monoamines, and muscarinic acetylcholine (Hirota and Lambert, 1996). Ketamine has garnered substantial interest as an antidepressant for treatment-resistant depression (Aan Het Rot et al., 2012; Hashimoto, 2014, 2015; Krystal et al., 2013). Indeed, a number of recent studies have demonstrated robust antidepressant effects of ketamine. In a randomized, double-blind, crossover clinical trial, Ionescu et al. (2014) treated anxious and non-anxious depressed patients with BP with a single infusion of ketamine (0.5 mg/ kg over 40 min). Both groups exhibited significant antidepressant responses, although those with anxious depression exhibited fewer depressive symptoms and a longer time to relapse (Ionescu et al., 2014). A recent study by Moaddel et al. (2015) demonstrated that baseline Dserine plasma levels were significantly lower in ketamine responders in comparison to non-responders, suggesting that D-Serine baseline plasma concentration may predict antidepressant response following ketamine administration (Moaddel et al., 2015). A randomized, double blind, crossover study by Lapidus investigated the efficacy of intranasal ketamine (50 mg) in patients with MDD who had failed at least one prior antidepressant trial, providing evidence for the rapid antidepressant effects of intranasal ketamine with minimal psychotomimetic or dissociative effects (Lapidus et al., 2014). A placebo-controlled, multiple crossover, double-blind study by Loo et al. (2016) demonstrated that intravenous, intramuscular, and subcutaneous administration of ketamine produced comparable antidepressant effects at doses as low as 0.1 mg/kg, with fewer adverse effects occurring via the subcutaneous route (Loo et al., 2016). In a randomized controlled trial of ketamine using an anesthetic control condition, Price et al. (2014) tested ketamine’s acute effects on explicit and implicit suicidal cognition, finding that ketamine induced rapid (within 24 h) reductions in suicidal cognition (Price et al., 2014), a finding that is striking given that conventional antidepressants (e.g., SSRIs) may actually worsen suicidal ideation in patients with MDD (Busch et al., 2010; Murphy et al., 2008). The mechanisms underlying ketamine’s rapid antidepressant effects go beyond NMDA receptor interactions. First, ketamine modulates AMPAR activity and, thereby, glutamatergic function in the medial prefrontal cortex. A single injection of ketamine (10 mg/kg) with fluoxetine and olanzapine increased AMPA and NMDA currents, with greater effects exhibited by AMPARs (Bjorkholm et al., 2015). Conversely, inhibition of AMPA function by 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide blocks antidepressant-like effects in rodents (Koike and Chaki, 2014). Also, ketamine administration stimulates mTOR signaling in the prefrontal cortex (Li et al.,

4.2. Memantine Memantine is a low-affinity, noncompetitive, open-channel NMDA antagonist that enters the receptor channel by binding to or near the Mg2+ binding site and blocks the NMDAR-associated ion channel. Originally, memantine was approved by the FDA for the treatment of Alzheimer's disease, but later studies in rodents revealed antidepressant-like effects (Quan et al., 2011; Reus et al., 2010), prompting its off-label use for various clinical disorders with mixed results (Gilling et al., 2009; Johnson and Kotermanski, 2006; Rammes et al., 2008; Zdanys and Tampi, 2008). Recently, Olivan-Blazquez assessed the efficacy of memantine to decrease symptoms of fibromyalgia in a double blind, parallel randomized trial with a 6-month follow-up. Results from the study demonstrated significant reductions in depressive symptoms, pain, and quality of life impairments (Olivan-Blazquez et al., 2014). In a randomized, double-blind, controlled, 12-week study, Lee investigated the effects of add-on memantine to valproic acid in persons with BP. Results demonstrated that valproic acid + memantine reduced TNF-α and low-density lipoprotein cholesterol but did not result in clinically significant changes in mania or depression scores (Lee et al., 2007; Lee et al., 2014). Stevens et al. (2013) evaluated the effect of memantine augmentation therapy for persons with BP II who were on a stable dose of lamotrigine in another randomized, double-blind, parallel-group, 8week study. Results demonstrated that patients who received memantine augmentation (titrated up by 5–20 mg/wk) exhibited an increased rate of response, with the maximum effect reached at 4 weeks, suggesting clinical utility by inducing a faster antidepressant response alongside other slower-acting medications (Stevens et al., 2013). In a double blind, placebo-controlled study, Zarate et al. (2006a,b) sought to determine the effects of low dose memantine (5–20 mg/day) for persons with MDD, finding no clinically significant effects on depressive symptoms (Zarate et al., 2006a). While memantine is generally well-tolerated with minimal side-effects (Parsons et al., 1999), the drug fails to induce rapid antidepressant effects (Ferguson and Shingleton, 2007; Lenze et al., 2012; Zarate et al., 2006b), suggesting that memantine and ketamine utilize different mechanisms of action. Indeed, recent electrophysiological analysis demonstrated that both ketamine and memantine antagonize the NMDAR at rest when Mg2+ is absent, but only ketamine blocks the NMDAR at rest when physiological concentrations of Mg2+ are present (Gideons et al., 2014). Moreover, memantine does not inhibit the phosphorylation of eEF2 or augment BDNF protein expression (Gideons et al., 2014), both of which are vital determinants of ketamine’s antidepressant efficacy. These findings suggest that the disparity in response between the two drugs may stem from their variable abilities to affect NMDAR function at rest under physiological conditions. 564

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that contribute to antidepressant effects. Indeed, current conceptualizations for ketamine’s mechanism of action suggest that NMDAR blockade of GABA-ergic interneurons in the cortex disinhibits major output neurons (e.g., cortical pyramidal cells) (Moghaddam et al., 1997). The disinhibition effectuates an increase in synaptic glutamate release/cycling (Chowdhury et al., 2012), which then favors AMPAR activity (Andreasen et al., 2013; Koike and Chaki, 2014; Maeng et al., 2008; Sanacora et al., 2008) along with the activation of several second-messenger cascades (e.g., monoamines, trophic factor signaling, synaptogenesis, neurogenesis, and inflammation) (Abelaira et al., 2014; Bjorkholm and Monteggia, 2016; Li et al., 2010b; Liu et al., 2004; Liu et al., 2016; Niciu et al., 2013).

4.3. Dextromethorphan Dextromethorphan is one of the antitussive ingredients used in many over-the-counter cold and cough medicines. It is a non-competitive NMDA antagonist with some sedative and dissociative properties and could potentially display fast-acting antidepressant properties (Lauterbach, 2011). Dextromethorphan modulates glutamate excitotoxicity by suppressing overactivity of the glutamatergic system centrally (Hollander et al., 1994). Bolstering this notion are in vitro studies showing that dextromethorphan antagonizes NMDA and glutamate-mediated excitation and excitotoxicity in the CNS and spinal regions. Also, dextromethorphan inhibits NMDA-induced convulsions and attenuates hypoglycemic neuronal injury (Fleming, 1986). One case report details how a patient with treatment-resistant MDD and loss of antidepressant response to fluoxetine and bupropion experienced a rapid-acting antidepressant effect within 48 h of dextromethorphan administration, an effect that lasted 7 days and was sustained 20 days with daily administration (Lauterbach, 2016). Chen et al. (2014) investigated the efficacy of valproic acid plus low-doses of dextromethorphan (30 or 60 mg/day) in persons with BP in a 12-week, randomized, double-blind study. Their results demonstrated that valproic acid plus low-dose dextromethorphan (30 or 60 mg/day) resulted in an improvement trend for both depression and mania symptoms, but the results were statistically significant only in the valproic acid plus 30 mg/day dextromethorphan group. Interestingly, there was also a trend for increased serum BDNF in both groups, but the results were statistically significant only in the valproic acid plus 60 mg/day dextromethorphan group (Chen et al., 2014). While the mechanisms underlying the effects of dextromethorphan have yet to be elucidated fully, some evidence suggests activation of mTOR, AMPAR trafficking, dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival (Lauterbach, 2011, 2012, 2016), although further investigations are needed to verify this notion.

5. Concluding remarks Decades of MD research that focused on the normalization of abnormalities in the MA-ergic system have produced antidepressants that have clinical utility but take weeks to achieve symptomatic relief and fail to provide symptomatic relief in more than half of individuals (Manji et al., 2001; Oswald et al., 1972; Paul and Skolnick, 2003; Trivedi, 2006). Therefore, the discovery that NMDAR antagonists exert rapid antidepressant effects in persons with MD (Berman et al., 2000; Price et al., 2009; Zarate et al., 2006a), treatment resistant depression (Price et al., 2009; Zarate et al., 2006a), and BP (Diazgranados et al., 2010) reinvigorated drug research and development efforts in the field. Further intensifying these investigations were discoveries that NMDAR antagonists reduce pro-inflammatory cytokines (Lee et al., 2014), increase BDNF levels and synaptogenesis (Autry et al., 2011; Garcia et al., 2008), and modulate AMPAR density and function. Notwithstanding, the high probability for abuse and neurotoxicity following an overdose (Ibrahim et al., 2012; Morgan et al., 2012), along with the lack of specificity for NMDAR subunits and resultant dissociative effects (Machado-Vieira and Mallinger, 2012), underscores the need for further research. Undoubtedly, the development of more effective NMDA-based therapeutics will be further supported by new studies seeking to i) understand the biological mechanisms underlying rapid NMDAR antagonist action, ii) identify the subtypes of NMDARs involved in MD pathophysiology, iii) develop highly specific blockers for NMDAR subtypes so as to minimize dissociative effects, vi) unravel the effects of genetic polymorphisms in NMDA signaling-related genes, v) determine reliable biomarkers that modulate NMDARs (e.g., BDNF, MORC family CW-type zinc finger 1 [known as MORC1]-signaling related molecules, and inflammatory cytokines) (Nieratschker et al., 2014), vi) derive new imaging tracers that target glutamate receptor binding to provide a means of assessment following administration of NMDAR antagonists, and vii) understand the interaction between NMDARs, trophic factors, and physical activity (Haile et al., 2014; Phillips et al., 2015; Phillips et al., 2014; Sanacora and Banasr, 2013) and their link to cognitive and behavioral changes associated with MDs (Phillips and Salehi, 2016). Indeed, a greater understanding of the synergy between these factors and the glutamatergic system will promote the development of multimodal therapies that comprehensively target depressive symptoms and minimize side effects. These advancements are imperative given that they have the potential to significantly reduce health- and disabilityrelated costs and improve overall quality of life for persons affected by MDs.

4.4. MK-0657/RDPC Originally, the NR2B subunit selective NMDA receptor antagonist MK-0657 was developed by Merck for the treatment of Parkinson's disease. Currently, an oral formulation of the drug is being investigated as an adjunctive therapy for treatment-resistant depression. Ibrahim et al. (2012) evaluated the efficacy of oral MK-0657 (4–8 mg/d for 12 days) in persons with treatment-resistant MDD in a pilot study and found significant antidepressant effects as early as day 5 in persons receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Rating Scale and Beck Depression Inventory. However, no significant effect was detected using the Montgomery-Asberg Depression Rating Scale (Ibrahim et al., 2012). These preliminary results suggest a potentially clinically meaningful treatment effect, but more work is needed to establish the efficacy of MK-0657 given that only five persons were included in the study. Despite their promise, glutamatergic modulators are not routinely recommended in clinical practice given the paucity of large multi-site, randomized, placebo-controlled trials. Studies of this type are needed to critically assess the efficacy, safety, and tolerability of glutamatergic modulators. However, some consider ketamine as a late option in the treatment of MDs with the goal of obtaining temporary symptom relief or as an alternative therapy for persons who are treatment-resistant. Admittedly, considerably more work is needed to ascertain the underlying mechanisms of action. Whereas ketamine shows a rapid and sustained antidepressant effect in patients with MDD or BD, the antidepressant effects of other NMDAR antagonists have been weaker than ketamine. The variable outcomes among the NMDAR antagonists may stem from their differential convergence on several synergistic mechanisms of action that together result in measurable behavioral outcomes. Such a view departs from the notion that NMDA antagonism is the only mechanism in favor of a view that encompasses other factors

Acknowledgments This research was supported by grants from the Lumind Research Down Syndrome and Lejeune Foundations, and Alzheimer’s Association and the WRIISC Program at the VA Palo Alto Health Care System (AS).

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