MDD may also involve an inability of neuronal systems, especially under stress conditions, to show adaptive plasticity, a mechanism known as neuronal plasticity [4
] (see Table ). Molecular correlations underlying the mechanisms of the stress response involve the regulation of several neurotrophic factors, one of them being brain-derived neurotrophic factor (BDNF). To this regard, several studies have demonstrated reduced serum and plasma BDNF levels in patients with MDD when compared with controls, and now a few studies have investigated BDNF at gene expression level. Pandey et al.
] investigated BDNF gene expression in both adult and pediatric patients with MDD and found significantly lower mRNA expression as well as lower protein levels in both MDD groups compared with controls [45
]. These findings are supported by another of our studies, where we have also shown significantly lower BDNF expression in the peripheral leukocytes of patients with MDD compared with controls [46
]. Additionally, we have found a significant increase in BDNF expression after treatment with the antidepressant escitalopram as well as a parallel improvement in depressive symptoms. In a similar study, we investigated the expression of the neuropeptide VGF (non-acronymic) in the peripheral leukocytes of patients with MDD and controls. VGF is known to be involved in synaptic plasticity and to be induced by BDNF [47
], and we have shown that VGF expression is significantly lower in patients with MDD compared with controls [48
]. Interestingly, we also found that expression of VGF is increased after 12 weeks of escitalopram treatment in those patients whose depressive symptoms were ameliorated. We have recently replicated these data in the aforementioned larger study [23
], where again we show that patients with MDD have lower mRNA levels of BDNF and VGF, and that antidepressant treatment (escitalopram or nortriptyline) increases both BDNF and VGF expression in treatment responders.
Studies examining alterations in the expression of genes involved in neuroplasticity
In a study of patients with MDD and BPD, Otsuki et al
. did not find any significant differences in BDNF expression between patients and controls [49
]. However, most of the patients were on antidepressant medication, so this may explain the lack of differences. Moreover, Otsuki and colleagues showed state-dependent differences in a number of other neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF), artemin (ARTN) and neurotrophin-3 (NT-3). These factors have previously been shown to be associated with stress response in animal models [50
] as well as with depression and suicide in humans [51
]. Specifically, they demonstrated that patients with MDD in a current depressive state have lower expression of GDNF, ARTN and NT-3 compared with those in remission as well as controls. However, they did not find any significant differences in the expression levels of these three factors in BPD patients in depressive or remissive states, suggesting that the changes in the expression of these genes are associated with MDD only, and may be state-dependent.
Another protein related to BDNF is p11, a member of the S-100 family known to be involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation [52
]. Interestingly, two studies have found p11 to be overexpressed in patients compared with healthy controls. Su et al
. demonstrated that patients with MDD had a higher expression of p11 compared with controls [54
], and Zhang et al
. found the same results in patients with BPD [55
]. However, in both of these studies the patients were medicated. Conversely, in our recent study we reported lower mRNA levels of p11 in drug-naïve patients with MDD compared with controls [23
]. Furthermore, after 8 weeks of antidepressant treatment, p11 levels were significantly increased. We have also recently demonstrated that p11 mRNA levels are increased by antidepressant treatment in vitro
in a human neuronal hippocampal model [43
], thus showing also the unique ability of a gene expression approach to be used consistently across different experimental approaches.
As mentioned earlier, the expression of neurotrophic factors can be altered particularly in response to oxidative or reductive stress. One such neurotrophic factor is vascular endothelial growth factor (VEGF). Increased expression of VEGF has previously been shown in peripheral monocytes of patients with diabetes with coronary artery disease [56
]. Given the high prevalence of depression in patients with coronary artery disease, VEGF mRNA levels have been proposed as a putative biological marker for MDD. Indeed, Iga and colleagues measured VEGF expression in the peripheral leukocytes of patients with MDD and showed that VEGF expression was higher in patients with MDD compared with healthy controls [57
]. A similar study by Dome et al.
] investigated the expression levels of VEGF receptor-2 (VEGFR2) in the peripheral blood of patients with MDD. They showed a lower expression of VEGFR2 in patients with MDD compared with healthy controls. Moreover, the expression of VEGFR2 negatively correlated with depression scores, thus supporting the role of VEGF signaling in MDD pathogenesis [58
Two further molecules regulating neurogenesis have been found to be altered in depression: pericentrin 2 (PCNT2) and epithelial membrane protein 1 (EMP1). PCNT2 is a disrupted in schizophrenia 1-interacting protein that regulates cell proliferation, differentiation and migration, and outgrowth of neuronal axons and dendrites. In a study of patients with MDD and BPD, mRNA levels of PCNT2 were found to be significantly higher in drug-naïve patients with MDD compared with controls [59
]. Interestingly, PCNT2 expression was also higher in patients with BPD in a remission state when compared with controls. EMP1 is involved in neurogenesis mechanisms as it interacts with transforming growth factor beta signaling. In drug-naïve patients with MDD, EMP1 levels were significantly lower when compared with controls and, after 8 weeks of antidepressant treatment, EMP1 mRNA levels showed a trend towards an increase [60
Cell adhesion molecules such as neural cell adhesion molecule (NCAM) and L1 are also known to play important roles in synaptic plasticity, and have been indicated to have altered expression in the cerebrospinal fluid and brain of patients with a mood disorder [61
]. Several studies conducted in peripheral blood mRNA confirm this. For example, Wakabayashi et al.
] assessed the expression of NCAM-140 and L1 in the leukocytes of patients with MDD and BPD, as well as controls. They found a lower expression of NCAM-140 in patients with BPD in a current depressive, but not in a remissive, state compared with both controls and patients with MDD [64
]. They also found a higher expression of L1, again in patients with BPD in a depressive state but not in those in remission compared with controls and patients with MDD. Interestingly, they did not find any significant differences in the expression of these molecules in patients with MDD when compared with controls. This suggests that the alterations in the expression of both NCAM-140 and L1 are specific to BPD and are also state dependent. In addition, no changes were found for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) or E-cadherin expression, in patients with either MDD or BPD compared with controls.
Repressor element-1 silencing transcription factor (REST) is a modulator protein that is also known to be involved in synaptic plasticity [65
]. It has been recently shown that REST is involved in the synthesis of cortisol [66
] and in neurogenesis [67
], both of which are of relevance to mood disorders. Otsuki and colleagues investigated the expression of REST and a variety of its target genes including corticotropin-releasing hormone (CRH), adenylate cyclise 5 (Adcy5) and TNF superfamily member 12-13 (TNFsf12-13) in patients with MDD and BPD [68
]. They found a lower expression of REST in patients with MDD compared with controls. Furthermore, they investigated whether altered expression of these mRNAs were state or trait dependent, reporting a higher expression of CRH, Adcy5 and TNFsf12-13 in patients with MDD in a current depressive state compared with those in a remissive state. Interestingly, they found no significant differences in the expression of REST or any other mRNAs in patients with BPD when compared with controls.