Review articleTargets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission
Graphical abstract
Introduction
Major depressive disorder (MDD) is a leading cause of disability worldwide (WHO, 2011). Multiple lines of evidence suggest that altered stress-coping mechanisms underlie the etiology of MDD by affecting neuronal communication in brain areas involved in the control of emotions and in stress response. Genetic and environmental factors, such as childhood trauma and chronic stress, can also increase the risk of developing MDD and may determine individual differences in response to diverse forms and durations of stress (Hammen, 2005, Hankin et al., 2007, Kendler et al., 1998, Tennant, 2002). Little is known about whether homeostatic mechanisms are affected in MDD stress response at the molecular level. In this review, we examine past and current evidence implicating a dysregulation of the polyamine system in MDD as a central factor in the etiology of MDD and in the homeostatic response to stress.
Polyamines (putrescine, spermidine, spermine, and agmatine) are ubiquitous, short, positively charged aliphatic amines that have fundamental roles in homeostatic mechanisms (Fig. 1). Their cellular roles include the regulation of gene transcription and post-transcriptional modifications, the modulation of synaptic activity, and the modulation of ion channels that participate in the excitability of neuronal networks (Table 1) and as reviewed by Pegg (Pegg, 2009). Polyamine levels are tightly regulated by two key rate-limiting enzymes – Ornithine decarboxylase (ODC1) and Spermidine/Spermine N1-acetyltransferase 1 (SAT1) (Fig. 2). ODC1 is the first enzyme in the synthesis of polyamines and produces putrescine from ornithine (Pegg, 2009); alternatively, putrescine can also be produced from agmatine by the enzyme agmatinase (AGMAT) (Sastre et al., 1996). Agmatine is also thought to be a neurotransmitter, with antagonistic effects at NMDA receptors and interactions with α2-adrenoreceptors (Reis and Regunathan, 2000), and has been shown to have antidepressant properties in animal models (Zomkowski et al., 2002), and in one clinical trial (Shopsin, 2013). Putrescine is the substrate to produce spermidine and spermine in sequential enzymatic reactions, while SAT1 is the rate limiting enzyme in the catabolism of polyamines (Pegg, 2009). Polyamine levels, particularly putrescine and agmatine, have been demonstrated to increase during stress, a phenomenon called the polyamine stress response (PSR) (Gilad and Gilad, 2003, Turecki, 2014). PSR magnitude is correlated with the intensity of the stressor and with the intensity of the behavioral response to stress, suggesting that a dysfunction of the polyamine system may be involved in the development of abnormal stress responses in conditions like MDD (Gilad and Gilad, 2003).
The effects of lithium in animal models and humans also evidence PSR alterations in MDD and suicide. Lithium is a commonly used mood stabilizer with significant anti-suicidal properties (Ahrens and Muller-Oerlinghausen, 2001, Bocchetta et al., 1998). Lithium has been shown to block PSR in the rodent brain when chronically delivered following dexamethasone treatment (Gilad and Gilad, 2003, Gilad et al., 1992b). A similar blockage of brain PSR is observed when lithium is administered pre or post the application of a stressful stimulus (Gilad and Gilad, 1996). Recently, Squassina and colleagues examined the effect of lithium on SAT1 gene expression in a cohort of lymphoblastoid cell lines which included cell lines from controls and subjects with bipolar disorder (Squassina et al., 2013). The bipolar subjects were grouped into three suicide categories: suicide completers, high suicide risk and low suicide risk. Seven-day lithium treatment increased SAT1 gene expression for all groups except the suicide completers, suggesting differential regulation of SAT1 in suicide completers.
Gene expression studies in post-mortem human brains have consistently supported an alteration of the polyamine system in MDD and suicide. The first study suggesting a dysregulation of the polyamine system in MDD-suicides showed significant decreases in gene and protein expression of SAT1 in the precentral gyrus (BA4) and cortical frontal lobe areas (BA11 and BA8,9) in both non-depressed suicides and MDD-suicides compared to controls (Sequeira et al., 2006). This finding has been confirmed by our group and several others across brain regions and several population groups (Fiori et al., 2011, Guipponi et al., 2009b, Klempan et al., 2009a, Klempan et al., 2009b, Pantazatos et al., 2015, Sequeira et al., 2007). It was also demonstrated that the rs6526342 SNP, located in the promoter regulatory region of SAT1, had a significant effect on gene expression and that this SNP was associated with suicide in a French-Canadian sample (Sequeira et al., 2006), known to have a founder population effect (Scriver, 2001). The genetic effect of the rs6526342 SNP on brain SAT1 gene expression was confirmed in French-Canadian (Fiori et al., 2009) and Mexican (Tovilla-Zárate et al., 2015) cohorts but, not in more genetically heterogeneous European cohorts (Guipponi et al., 2009a), suggesting the presence of other genetic variants involved in the control of SAT1 gene expression. Other genetic association studies also showed an association between ODC1 SNPs (rs1049500 and rs2302614) and suicide attempts (Sokolowski et al., 2013). Ornithine decarboxylase antizyme 1, and 2 (OAZ1 and OAZ2), enzymes that control ODC1 activity by degradation (Fig. 2), have also been found to be upregulated in suicide completers across multiple psychiatric diagnoses including MDD (Gross et al., 2013). Moreover, gene expression of AMD1, which participates in the synthesis of spermidine and spermine from putrescine is altered in middle temporal cortex (BA21) of MDD individuals (Aston et al., 2005). Overall, these gene expression changes suggest abnormal concentrations of polyamines in MDD. Concordantly, putrescine and spermidine levels were significantly elevated in cortical areas (BA4, BA8,9, and BA11) of male MDD-suicide victims when compared to controls (Chen et al., 2010) and suggest that abnormal metabolism of polyamines might be involved in the pathophysiology of suicide and MDD by modulating stress response. Henceforth, we will discuss the polyamine system in the context of its role in sensing and controlling of neuronal electrical activity and its involvement in MDD and suicide.
Section snippets
Signatures of brain activity in MDD
Neuroimaging studies have shown that the strength of functional, reciprocal connectivity between the amygdala, a region critical in the generation and processing of negative emotions, and frontal cortical regions, which are involved in the modulation of amygdala reactivity and cognitive interpretation of negative stimuli, predicts successful emotional regulation (Banks et al., 2007, Comte et al., 2016, Hariri et al., 2002). Similar studies in people with MDD have shown amygdala hyperactivity at
Polyamines in activity-feedback mechanisms
While the role of polyamines on synaptic and ion channel modulation is well known, their role in activity-feedback mechanisms that control neuronal firing rate is somewhat less recognized. Evidence from the past three decades shows that firing rate and ODC1 activity are tightly correlated across a broad range of excitability levels, from small changes of ODC1 occurring during physiological stimulation of visual pathways, to large increments (≥50-fold) during epileptiform activity (Baudry et
Modulation of neuronal excitability by cytosolic polyamines
Polyamines modulate a broad range of neurotransmitter receptors and ion channels that permeate cations (Table 1). Some polyamine targets drive excitability (e.g. Voltage gated Na+ and Ca2+ channels, ionotropic glutamate and nicotinic receptors) and others maintain resting membrane potential and modulate neuronal firing rate (e.g. inward rectifiers K+ channels). Therefore, the net effect of polyamine levels on neuronal excitability depends on the particular set, and proportions, of membrane
Modulation of synaptic activity by extracellular polyamines
Polyamines reach the extracellular space by Ca2+-independent and Ca2+-dependent efflux processes (Fage et al., 1992, Fage et al., 1993, Harman and Shaw, 1981). Ca2+-dependent processes can be triggered by depolarization of the membrane via activation of NMDA receptors or blockade of Na+/K+ transporters (Fage et al., 1992, Fage et al., 1993, Masuko et al., 2003). Additionally, at highly depolarized voltages internal polyamines can permeate through Ca2+-permeable AMPA receptors resulting in the
Role of polyamines in stress response and depression
It is well known in animal models that stress activates both the amygdala and the HPA axis, and triggers the PSR, it is not very clear however how regional increases in activity and the PSR are mechanistically linked. Based on the available evidence, activation of the amygdala-HPA axis during stressful events increases neuronal firing and cytosolic [Ca2+], which, consequently, will produce a fast, neuroprotective increase in ODC1 activity and synthesis of polyamines that would reduce the open
Conclusions
In this review, we summarize evidence in support of an allostatic model of depression. According to this model, chronic elevations of polyamine levels result in a self-sustained stress response which is maintained by maladaptive homeostatic mechanisms (Fig. 4). Specifically, in vulnerable individuals exposure to chronic or acute stress can lead to hyperexcitabity of the amygdala, which will induce a persistent elevation of ODC1 gene expression leading to subsequent increases in polyamine levels.
Acknowledgments
The research was supported by The Brain & Behavior Research Foundation (former NARSAD) Young Investigator Award (AS) and by NIMH research grant R01MH097082 (AS).
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2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Interestingly, the modulation of AMPA receptors is probably involved in the antidepressant effect of arketamine, the R(−)-enantiomer of ketamine, in line with the hypothesis that the effect of ketamine in depression does not solely depend from NMDA receptors inhibition (Leal et al., 2020). Polyamine levels have been demonstrated to increase during stress, a phenomenon called the polyamine stress response, and they have been implicated in MDD and suicide (Limon et al., 2016). Spermidine is also involved in the regulation of aging and external supply of polyamines may protect against age-related memory loss, representing a possible therapeutic intervention that is currently under investigation (Wirth et al., 2019).