The present review seeks to bridge the gap between recent findings that implicate both impairments in synaptic plasticity and increased levels of proinflammatory cytokines in patients with mood disorders. As this paper has explored, we propose that cytokine-induced impairments in synaptic plasticity may underlie at least some aspects of the complex pathophysiology of MDD based on the evidence that: (1) elevation of brain cytokine levels is necessary and sufficient to induce depressive symptoms and neuro-endocrine changes in animal models of depression; (2) increased levels of brain cytokines have been shown to impair synaptic plasticity both at morphological and functional levels; and (3) cytokine-induced modulation of neurotransmission and synaptic plasticity plays an important role in the mechanism of antidepressant action and the efficacy of antidepressant treatment.
It is important to note that although the increased levels of cytokines seen in patients with MDD are detrimental to neuroplasticity, physiological levels of pro-inflammatory cytokines are essential for normal brain development and homeostatic regulation of synaptic scaling (Avital et al. 2003
; Beattie et al. 2002
; Goshen et al. 2007
; Stellwagen & Malenka, 2006
). These two conflicting pieces of evidence suggest that it is the disturbance of this intricate equilibrium between physiological and pathophysiolgical levels of cytokines in the brain that affects synaptic plasticity and plays a critical role in the pathophysiology of MDD ().
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 (more ...)
In the context of this review, it is important to note that despite the accumulating evidence in support of the cytokine hypothesis of MDD, several studies have found only a weak association, or no association, between inflammation and the development of depression when factors such as body mass index, gender, and personality were taken into account (Brambilla & Maggioni, 1998
; Carpenter et al. 2004
; Miller et al. 2003
; Rothermundt et al. 2001
). In addition, some otherwise positive studies failed to find a correlation between inflammation and the severity of depressive symptoms (Hestad et al. 2003
), or found disparate and occasionally opposing correlations for different pro-inflammatory mediators (Miller et al. 2002
; Pollmacher et al. 2002
Another issue that remains to be elucidated is whether pro-inflammatory cytokines, released peripherally upon immune system activation, play a causal role in the onset of MDD, or whether they represent an immunological side-effect of this disease. Indeed, due to the associative nature of the studies investigating the relationship between immune activation, cytokines, and MDD it is unclear whether the activation of the immune system observed in depressed patients precedes or follows the onset of depressive disorders (reviewed in Dantzer et al. 2008
; Raison et al. 2006
). However, the findings that cytokine therapy is often accompanied by adverse psychiatric events, which disappear when cytokine treatment ends or antidepressant treatment begins, suggest a potentially causal role for pro-inflammatory cytokines in the aetiology and pathophysiology of mood disorders; the observation that anti-cytokine treatment produces an antidepressant response in patients with MDD and BPD lends further credence to this notion.
Future research will need to determine the clinical effects of cytokine antagonists on the pathophysiological and psychological features of mood disorders. In order to elucidate the functional role of cytokine-induced alterations of synaptic plasticity in the pathophysiology of MDD, it will also be important to identify the effects of cytokine antagonists and cytokine synthesis inhibitors on neuroplasticity, both at the morphological and functional level. 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.