염증과 glutamate의 신경손상 기전과 기분장애 유발

[현준]

Haroon E, Miller AH, Sanacora G. Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology. 2017 Jan;42(1):193-215. doi: 10.1038/npp.2016.199. Epub 2016 Sep 15. PMID: 27629368; PMCID: PMC5143501.

Abstract

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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.

염증과 glutamate 신경전달과정의 변형은 기분장애(Mood disorders)의 원인의 되는 병리기전이다.

glutamate가 지나치게 많이 분비되고, 방출된 glutamate가 정상적으로 제거가 잘 안되는 것은 glutamate의 누적을 초래한다.

누적되어 많아진 glutamate는 비정상적인 시냅스외 신호전달을 촉진하고 결과적으로 시냅스 기능장애와 시냅스의 파괴를 만들어낸다.

Glutamate의 조절은 신경교세포(glia)의 핵심적인 역할이다.

염증은 신경교세포와 glutamate에 영향을 끼쳐 기분장애를 유발한다.

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Figure 1
Impact of inflammation on glutamate neurotransmission and synaptic integrity. Left panel depicts the glutamatergic synapse at an early stage of inflammation. High levels of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1β released by activated inflammatory cells including microglia, astroglial, and macrophages lead to increases in the concentration of synaptic glutamate (GLU), toxic kynurenine molecules with glutamate-like effects such as quinolinic acid (QUIN), and reactive oxygen (ROS)/nitrogen (RNS) species leading to oxidative stress. Effects of inflammatory molecules upon astrocytic cell morphology leads to decreased ability to ‘cradle', sequester, and contain glutamate within the synapse resulting in a spillover of the glutamate into the extrasynaptic space. Concurrent decreases in the number and functioning of excitatory amino-acid transporters (EAAT) 2-induced by inflammation further limits the ability of astrocytes to buffer and clear the spillover glutamate. Additional release of glutamate by increased xC-activity alone or in combination with reverse effluxive release via EAATs by immune-activated glial cells further adds to the concentrations of extrasynaptic glutamate available to diffuse and bind to extrasynaptic binding sites. Increases in synaptic glutamate resulting from early inflammatory changes are shown as leading to the overactivation of intrasynaptic ionotropic receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate receptors (NMDA) potentially contributing to excitotoxicity. The spillover glutamate is also shown as binding to the extrasynaptic NMDA receptors leading to suppression of neurotrophic support from factors such as brain-derived neurotrophic factor (BDNF). Some of the excess glutamate is also seen binding to presynaptic metabotropic glutamate receptors (mGluR2/3), which provides negative feedback to block further glutamate release as shown in the right panel.


Right panel depicts the glutamate synapse at a late stage of chronic inflammation. The progression of glutamatergic dysfunction has resulted in an overall loss of glutamate neurotransmission. Sustained stimulation of presynaptic mGluR2/3 systems by glutamate diffusing through extrasynaptic space leads to inhibition of excitatory neurotransmission and increased trapping of glutamate in the vesicles within the presynaptic membrane. The toxic effect of overstimulation of intrasynaptic AMPA during early immune activation has led to a downregulation, desensitization, and atrophic loss of intrasynaptic AMPA receptors. Decreasing intrasynaptic glutamatergic activity also leads to the loss of intrasynaptic NMDA signaling even while the extrasynaptic NMDA signaling continues to remain high. This altered ratio of intrasynaptic to extrasynaptic signaling leads to atrophy and regional loss of neurons seen in patients with mood disorders as seen in the shrinking postsynaptic neuron. Finally, the persistently increased extrasynaptic glutamate, increased ROS/RNS, and QUIN also contribute to astrocytic and oligodendrocyte toxicity leading to atrophic changes in these cells as well.

좌측그림

다양한 염증세포에 의해 생긴 높은 농도의 사이토카인은 시냅스에 높은 농도의 glutamate와 독성물질(QUIN), 활성산소가 생기게 한다. 또한 염증은 성상세포에 안좋게 작용하여 성상세포가 glutamate를 많이 방출하고 방출된 glutamate를 제거하고 흡수하는 기능을 제한시킨다.

결과적으로 염증에 의해 시냅스 사이 공간에 glutamate와 활성산소 등 안좋은 물질의 누적과 신경전달과정에서 안좋은 작용들이 촉진된다.

우측그림

장시간 누적된 glutamate와 안좋은 반응, 안좋은 물질들(ROS, QUIN)은 neuron의 위축과 소실을 초래한다.

기분장애 환자는 시냅스 후 뉴런이 위축되고 손상되어 있다. 또한 신경전달과정에서 중요한 역할을 하는 성상세포(Astrocyte), 희소돌기아교세포(Oligodendrocyte) 도 이러한 독성들에 위해 위축성변화를 겪게 된다. (파괴되고 소실됨)

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Astrocytic Dysfunction and Mood Disorders

A robust literature exists supporting the association between astrocytic dysfunction and mood disorders in general, and has been extensively reviewed elsewhere (Ongur et al, 2014; Popoli et al, 2012; Rajkowska and Miguel-Hidalgo, 2007; Rajkowska and Stockmeier, 2013; Sanacora and Banasr, 2013; Verkhratsky et al, 2014). Major highlights of this literature are provided in Box 1.

성상세포의 기능장애와 기분장애(mood disorders)사이에는 상관관계가 있다.

기분장애가 있는 환자들은 성상세포가 기능장애, 위축되어 있을 가능성이 높다.

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Oligodendrocytes and Glutamate

Similar to neurons, oligodendrocytes are highly vulnerable to glutamate toxicity. Glutamate toxicity to oligodendrocytes may be precipitated by oxidative stress or direct ionotropic receptor-mediated excitotoxicity (Oka et al, 1993; Takahashi et al, 2003b). Oligodendrocyte cell toxicity might be mediated by the overstimulation of AMPA and kainate receptors located on the oligodendrocyte cell body, whereas impaired myelin synthesis might result from toxic activation of NMDA receptors densely represented in the branching processes (Matute et al, 2006; Verkharatsky and Butt, 2013). Although cell death from glutamate overactivation of AMPA/kainite receptors is of interest in the study of demyelinating disorders, toxicity from oligodendrocytic NMDA receptors might be of interest to psychiatry, as these receptors are located on the oligodendrocyte branches that are active myelin-synthesizing regions (Matute, 2006). Similar to astrocytes, increases in inflammatory cytokines such as TNF and IL-1β are known to impair glutamate buffering and clearance by oligodendrocyte EAATs, and trigger glutamate toxicity (Takahashi et al, 2003a; Takahashi et al, 2003b). Indeed, inhibition of the expression‎ and functioning of glutamate transporters such as EAATs and xC-transporters in axonal tracts is sufficient to induce oligodendrocyte loss and demyelination, which undermines brain connectivity (Domercq et al, 2007; Evonuk et al, 2015).

oligodendrocyte도 뉴런과 비슷하게 glutamate 독성에 취약하다.

Oligodendrocytes and Mood and Other Disorders

Varying degrees of myelin loss and decreasing function and/or numbers of oligodendrocytes have been reported among patients with mood disorders and schizophrenia (Edgar and Sibille, 2012; Rajkowska et al, 2015; Tavares et al, 2002). Oligodendrocyte cells contain substantial quantities of iron, which make them highly vulnerable to oxidative stress through the generation of reactive oxygen species. Transferrin—an iron binding, mobilization, and detoxification protein—was underexpressed in the oligodendrocyte cells in the internal capsule of patients with bipolar disorder (Barley et al, 2009). Of note, transferrin is also an acute-phase protein, which is depleted during immune activation (Ritchie et al, 1999). Oligodendrocyte loss accounts for a high proportion of the cell loss in the amygdala in major depression (Hamidi et al, 2004).

기분장애환자 조현병환자를 조사해보았더니 myelin이 감소되어 있고 oligodendrocyte의 기능장애도 같이 있던 경우가 많이 보고되어있다.

MOLECULAR MECHANISMS OF GLUTAMATE CLEARANCE

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EAATs

EAATs are specialized transport proteins expressed on the synaptic surface of neurons and glial cells that remove and detoxify glutamate from the synaptic (and to a lesser extent extrasynaptic) space in a matter of milliseconds into the glial cells (Nedergaard et al, 2002). There are at least five different types of EAATs described with specific patterns of cellular localization. EAAT2 and EAAT1 have primarily been localized to astrocytes and oligodendrocytes, respectively, and EAAT3–4 and EAAT5 are primarily localized to neurons (Arriza et al, 1997; Danbolt, 2001). It has been estimated that almost 80% of the glutamate released by presynaptic neurons under homeostatic conditions is cleared by EAAT2 reuptake into astrocytes and up to 20% by EAAT3 into neurons (Danbolt, 2001).

시냅스에서 분비된 glutamate는 EAATs 라는 수송체 단백질에 의해 제거되고 독성이 제거된다.

일반적인 조건하에서 분비된 glutamate의 80%는 성상세포로, 20%는 뉴런으로 재흡수된다.

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CONCLUSIONS AND FUTURE DIRECTIONS

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Extensive data indicate that the immune system has multiple roles in the regulation of glutamate neurotransmission and the maintenance of synaptic integrity. In addition, glutamate can profoundly influence the function of immune cells in the brain including microglia. Relevant to pathology, increased activation of the immune response in the periphery and CNS can lead to marked alterations in glial function and glutamate regulation, and through the activation of multiple avenues of excitotoxicity can lead to synaptic dysfunction and death, and ultimately behavioral and cognitive impairments. Much interest has focused on the role of these interactions among inflammation, glutamate metabolism, and glial function in mood disorders. However, studies have failed to fully establish whether inhibition of inflammation can reverse CNS glutamate changes as assessed by neuroimaging strategies such as MRS. Moreover, it remains unclear whether and which markers of inflammation might identify those patients who are most likely to respond to glutamate-targeted therapies. In addition, the contribution of inflammation-induced changes in glutamate to white matter pathology remains unclear. Finally, further examination of how treatments that target inflammation and glutamate can be combined or sequenced to achieve lasting response or disease prevention is warranted. In summary, it has become increasingly clear that there are many more pathways to pathology in mood and other neuropsychiatric disorders that go beyond the monoamines. Inflammation and its effect on glia and glutamate are two of these pathways, and data indicate that there is an important convergence that if recognized and studied may greatly enhance the further development of therapeutics that target these pathways.

증가된 면역반응, 염증반응은 말초와 중추신경계에서 신경교세포의 기능을 변형시키고 glutamate의 적절한 조절 능력을 변형시킨다.

그리고 이 과정에서 생기는 glutamate의 과잉,Spilover에 의한 흥분독성의 여러가지 경로들을 활성화 시켜 결과적으로 시냅스 기능 장애와 손상과 파괴를 초래합니다. 이러한 결과들은 궁극적으로 행동 및 인지 장애를 초래할 수 있다. (Mood disorders)

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요약

신경계의 염증반응은 신경세포내 glutamate가 과잉누적되게 하고, 이러한 상황이 오랫동안 지속된다면 신경전달과 관련된 여러 세포들이 손상되고 기능장애가 발생한다.

이러한 상황은 Mood disorders의 유발원인이 되는것으로 생각된다.

즉 염증에 의한 glutamate의 누적은 기분장애의 유발요인이다. -> glutamate 양을 줄여주거나 조절기능을 회복시키면 기분장애 치료에 도움이 될 수 있다.