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During the past two decades, there has been increasing interest in understanding and characterizing the role of inflammation in major depressive disorder (MDD). Indeed, several are the evidences linking alterations in the inflammatory system to Major Depression, including the presence of elevated levels of pro-inflammatory cytokines, together with other mediators of inflammation. However, it is still not clear whether inflammation represents a cause or whether other factors related to depression result in these immunological effects. Regardless, exposure to early life stressful events, which represent a vulnerability factor for the development of psychiatric disorders, act through the modulation of inflammatory responses, but also of neuroplastic mechanisms over the entire life span. Indeed, early life stressful events can cause, possibly through epigenetic changes that persist over time, up to adulthood. Such alterations may concur to increase the vulnerability to develop psychopathologies. In this review we will discuss the role of inflammation and neuronal plasticity as relevant processes underlying depression development. Moreover, we will discuss the role of epigenetics in inducing alterations in inflammation-immune systems as well as dysfunction in neuronal plasticity, thus contributing to the long-lasting negative effects of stressful life events early in life and the consequent enhanced risk for depression. Finally we will provide an overview on the potential role of inflammatory system to aid diagnosis, predict treatment response, enhance treatment matching, and prevent the onset or relapse of Major Depression.

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Background:Major depression is associated with several alterations, including reduced neuronal plasticity and impaired synaptic function, which represent an important target of pharmacological intervention.Methods:In the present study, we have investigated the ability of the antipsychotic drug lurasidone to modulate behavioral and neuroplastic alterations in the chronic mild stress model of depression.Results:Rats that show reduced sucrose consumption after 2 weeks of chronic mild stress have reduced expression of the pool of Bdnf transcripts with the long 3′ untranslated region (3′-UTR) that may be targeted to the synaptic compartment, suggesting the contribution of the neurotrophin to the behavioral dysfunction produced by chronic mild stress. The downregulation of Bdnf expression persisted also after 7 weeks of chronic mild stress, whereas chronic lurasidone treatment improved anhedonia in chronic mild stress rats and restored Bdnf mRNA levels in the prefrontal cortex. Moreover, chronic lurasidone treatment was able to normalize chronic mild stress-induced defects of Psd95 and Gfap as well as changes in molecular regulators of protein translation at the synapse, including mTOR and eEF2.Conclusions:These results demonstrate that lurasidone shows antidepressant properties in the chronic mild stress model through the modulation of synaptic and neuroplastic proteins. Such changes may contribute to the amelioration of functional capacities, which are deteriorated in patients with major depression and stress-related disorders.

Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoformspecific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.Major depression is believed to originate from the interaction between susceptibility genes and environmental events. Genetic susceptibility may be due, at least in part, to deficits in neuronal resiliency and neuroprotective responses or, alternatively, to exacerbated function of systems that may lead to neuronal dysfunction and psychopathology (Duman, 2009). There is mounting evidence suggesting that heightened susceptibility in mood disorders can be due to impaired neuronal plasticity, driven by reduced expression and function of key mediators, such as the neurotrophin brain-derived neurotrophic factor (BDNF), which are important for cellular resilience (Tsankova et al., 2006;McClung and Nestler, 2008;Pittenger and Duman, 2008;Calabrese et al., 2009). Moreover, the modulation of BDNF represents a crucial step in long-term adaptive changes brought about by antidepressant drugs (Calabrese et al., 2007Castrén et al., 2007;Kozisek et al., 2008;Molteni et al., 2009). Although there is a general agreement that antidepressant drug treatment can modulate the expression of BDNF, controversies exist with regard to the magnitude, timing, and anatomical specificity of such changes Groves, 2007;Martinowich et al., 2007;Kozisek et al., 2008; ABBREVIATIONS: SERT, serotonin transporter; KO, knockout; WT, wild type; BDNF, brain-derived neurotrophic factor; DLX, duloxetine; PCR, polymerase chain reaction; ANOVA, analysis of variance; SCPHT, single-contrast ...

BackgroundGrowing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of depression. Indeed, depressed patients exhibit increased levels of inflammatory markers in both the periphery and the brain, and high comorbidity exists between major depression and diseases associated with inflammatory alterations. In order to characterize the link between depression and inflammation, we aimed to investigate whether an altered inflammatory system is present in a genetic model of vulnerability for depression, namely rats with partial or total deletion of the serotonin transporter (SERT) gene.MethodsWild-type, heterozygous and homozygous SERT rats were analyzed under basal condition or following a challenge with an acute injection of lipopolysaccharide (LPS) and killed 24 h or 5 days later.ResultsWe found that SERT mutant rats show altered cytokine expression in the dorsal and ventral hippocampus at basal conditions, and they also display an exacerbated cytokine response to the LPS challenge. Moreover, mutant rats exhibit differences in the expression of markers for microglia activation.ConclusionBased on these data, we suggest that basal or functional alterations of immune/inflammatory systems might contribute to the phenotype of SERT rats and to their heightened susceptibility to depressive-like behavior.

Gene expression changes are well documented in depression and schizophrenia and might contribute to the pathologic phenotype associated with these disorders. On this basis, the investigation of transcriptional changes is extensively employed at the preclinical level in order to identify and characterize genes causally related to a pathologic condition. Key information can be achieved with respect to functional alterations in selected brain structures and to anatomical networks and systems that are altered in mental disorders. Furthermore, such analyses are used to investigate the impact of pharmacologic intervention in mechanisms that are significantly impaired in the disease or that might contribute to their therapeutic effectiveness. In this review, we will primarily discuss target approach analyses as a valuable instrument to address key questions in experimental work. We will focus on a few paradigmatic examples, such as the modulation of the neurotrophin brain-derived neurotrophic factor and the regulation of inducible early genes and the functional implication of such analyses. We will also briefly discuss genome-wide approaches that aim at identifying, in an unbiased manner, all the genes differentially affected under a given experimental setting.

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