A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder

Abstract

A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder (MDD). Several pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) have been found to be significantly increased in patients with MDD. This review focuses on these two cytokines based on multiple lines of evidence from genetic, animal behaviour, and clinical studies showing that altered levels of serum TNF-alpha and IL-1 are associated with increased risk of depression, cognitive impairments, and reduced responsiveness to treatment. In addition, recent findings have shown that centrally expressed TNF-alpha and IL-1 play a dual role in the regulation of synaptic plasticity. In this paper, we review and critically appraise the mechanisms by which cytokines regulate synaptic and neural plasticity, and their implications for the pathophysiology and treatment of MDD. Finally, we discuss the therapeutic potential of anti-inflammatory-based approaches for treating patients with severe mood disorders. This is a promising field for increasing our understanding of the mechanistic interaction between the immune system, synaptic plasticity, and antidepressants, and for the ultimate development of novel and improved therapeutics for severe mood disorders.

Figures

Fig. 1

Dual role of pro-inflammatory cytokines in regulating synaptic plasticity. The diagram on the left depicts the critical role of constitutively expressed TNF-α in regulation of homeostatic synaptic plasticity in the normal brain. Decreased neuronal activity and consequently reduced glutamate release from axons is sensed by glia, which triggers release of TNF-α. TNF-α activates neuronal TNF-α receptors type I (TNFR1) leading to activation of the phosphoinositide-3 kinase (PI3K) pathway and up-regulation of specific adhesion molecule-β3 integrin, which in turn triggers α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor insertion to the membrane and increases synaptic strength. The diagram on the right depicts the various signalling cascades initiated by high pathophysiological levels of pro-inflammatory cytokines in the brain by activated microglia, which might underlie at least some aspects of the pathophysiology of depression. (1) TNF-α and IL-1 trigger production of quinolinic acid and release of glutamate by microglia; (2) TNF-α and IL-1 inhibit glutamate removal by astrocytes, leading to excess extracellular glutamate and neurotoxicity; (3) TNF-α acts via TNFR1 to up-regulate membrane expression of Ca-permeable AMPA receptor subunits, thus leading to increased Ca2+ influx and neuronal death; (4) TNFR1 activation coupled to activation of p38 and NF-κB pathways inhibits the early and late phases of LTP. These effects of pathophysiological levels of pro-inflammatory cytokines on synaptic plasticity at both morphological and functional levels might underlie the cognitive disturbances and impairments of memory seen in patients with depression.