Integrating neuroimmune systems in the neurobiology of depression

Wohleb, Eric S.; Franklin, Tina; Iwata, Masaaki; Duman, Ronald S.

doi:10.1038/nrn.2016.69

Cited by 547 publications

(421 citation statements)

References 226 publications

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“…Unfortunately, current main antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic anti-depressants (TCAs), display unsatisfactory response rates and various side effects [2]. Although the etiology and pathophysiology of depression remain unknown, recent evidence suggests that inflammation can affect the brain and play a vital role in the psychopathology of depression [3, 4]. The previous reports from our and other laboratories have identified the underlying role of several endogenous alarmins or damage-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1) [5–7] and adenosine triphosphate (ATP) [8], in neuroinflammation and depressive symptoms.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

Gong

Cao

et al. 2018

J Neuroinflammation

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BackgroundDepression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression.MethodsAfter 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo.ResultsFour-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia.ConclusionsThese data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1296-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

Gong

Cao

et al. 2018

J Neuroinflammation

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“…In vitro studies of primary hippocampal neurons have shown that TNF signaling controls synaptic scaling by increasing trafficking of AMPA glutamate receptors and decreasing the numbers of surface GABA receptors (Wohleb et al, 2016). Experimental application of TNF to hippocampal slices induced a rapid increase in excitatory postsynaptic electrical activity mediated by increased expression of overactive surface AMPA receptors (Beattie et al, 2002) associated with an overrepresentation of GluA1compared with GluA2subu-nits (Vezzani and Viviani, 2015).…”

Section: Tnfmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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“…Furthermore, a CTNNA2 SNP was associated with BD in a GWAS study [58]. IL34 is a cytokine that is implicated in immune response and might play an important role in inflammatory mechanisms in mood disorders [59,60]. For instance, IL34 cytokine is important for the survival of microglia, the macrophages of the brain that determine the levels of inflammation in the cellular environments [61].…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

et al. 2017

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Mitochondrial DNA mutations have been reported to be associated with bipolar disorder (BD). In this study, we performed genome-wide analyses to assess mitochondrial single-nucleotide polymorphism (mtSNP) effects on BD risk and early-onset BD (EOBD) among BD patients, focusing on interaction effects between nuclear SNPs (nSNPs) and mtSNPs. Common nSNP and mtSNP data from European American BD cases (n = 1,001) and controls (n = 1,034) from the Genetic Association Information Network BD study were analyzed to assess the joint effect of nSNP and nSNP-mtSNP interaction on the risk of BD and EOBD. The effect of nSNP-mtSNP interactions was also assessed. For BD risk, the strongest evidence of an association was obtained for nSNP rs1880924 in MGAM and mtSNP rs3088309 in CytB (p_joint = 8.2 × 10^-8, p_int = 1.4 × 10^-4). Our results also suggest that the minor allele of the nSNP rs583990 in CTNNA2 increases the risk of EOBD among carriers of the mtSNP rs3088309 minor allele, while the nSNP has no effect among those carrying the mtSNP major allele (OR = 4.53 vs. 1.05, p_joint = 2.1 × 10^-7, p_int = 1.16 × 10^-6). While our results are not statistically significant after multiple testing correction and a large-sample replication is required, our exploratory study demonstrates the potential importance of considering the mitochondrial genome for identifying genetic factors associated with BD.

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Integrating neuroimmune systems in the neurobiology of depression

Cited by 547 publications

References 226 publications

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

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