Targeting resiliency at the cellular level can be accomplished through a variety of mechanisms, including (but not exclusively) neurotrophic, survival, and GR signaling pathways (see ). Here, cellular resiliency is broadly defined as a cell's ability to adapt to different insults that are caused by the environment, which may be exacerbated (or attenuated) by certain inherited or developed factors. Furthermore, targeting resiliency as a mechanism to treat BPD is well-supported in the literature through neuroimaging and neuropathological studies. The neuroimaging and neuropathological findings reviewed below suggest that, in BPD, loss of cellular plasticity may be due to loss of trophic support or survival factors coupled with additional mechanisms such as disrupted intracellular signaling cascades.
Specifically, neuroimaging data support reductions in gray matter in the subgenual anterior cingulated cortex (sgACC) of patients with MDD or BPD, regardless of mood state (Drevets et al., 2008
). Additional imaging studies have also shown abnormalities in the PFC, ventral striatum, hippocampus, and third ventricle (Beyer and Krishnan, 2002
; Drevets, 2001
; Strakowski et al., 2002
). In patients with BPD, decreased regional cerebral blood flow (rCBF) in the orbitofrontal cortex coupled with increased rCBF in the dorsal anterior cingulated cortex associates with biological correlates of emotional vulnerability (Kruger et al., 2006
). Interestingly, hypoactivity of the orbitofrontal cortex has been associated with shifts between euphoric and dysphoric mood states as well as the inability to distinguish between relevant and irrelevant emotional stimuli (Angrilli et al., 1999
; Grafman et al., 1986
; Joseph, 1999
Neuropathological studies of individuals with MDD or BPD indicate decreased gray matter volume and reduced glia in the sgACC, but no impact on neuronal number (Drevets et al., 2008
). Rajkowska et al. (2001)
, concentrating on the dorsal lateral PFC, found reduced neuronal density in layer III, and reduced pyramidal cell densities in layers III and V, in addition to reductions in glial densities in sublayer IIIC and enlarged glial shapes in patients with BPD compared to controls (Rajkowska et al., 2001
). Because these changes may be progressive over the course of the illness, preventing these reductions by engaging resiliency mechanisms could slow or disrupt the progression of BPD.
2.1. Common molecular targets of mood stabilizers
The two mood stabilizers most often used to treat BPD are lithium and valproate. These structurally dissimilar molecules (cation versus fatty acid) share common targets that may underlie their clinical benefits. Chronic lithium treatment has been shown to upregulate Bcl-2 (Manji et al., 2000
), Bag-1 (Zhou et al., 2005
), and Fkbp5 (McQuillin et al., 2007
) in addition to downregulating mRNA coding for post-synaptic 5-HT(1A) receptors in the rat hippocampus (McQuade et al., 2004
). Similarly, chronic valproate treatment upregulates BAG-1 (Zhou et al., 2005
) and Bcl-2 (Chen et al., 1999
), although the direct mechanisms remain unclear. Treatment of mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus (MMTV)-chloramphenicol acetyltransferase reporter plasmid (LMCAT), with lithium (1–4 mM) or valproate (0.1–3 mM) inhibits corticosterone-induced activity of the reporter gene (Basta-Kaim et al., 2004
). This further supports lithium and valproate's inhibitory effects on corticosterone-induced mechanisms that may enhance GR function in suppressing over activity of the HPA axis. highlights three prominent signaling cascades that are affected by mood stabilizer treatment (e.g., the Bcl-2 family, brain-derived neurotrophic factor (BDNF) neurotrophic/neuroprotection, and glucocorticoid receptor signaling cascades). Many examples of pathway interaction and convergence are demonstrated, especially surrounding mitochondrial membrane integrity, which is a critical target of cell survival and death mechanisms.
2.2. Anti-apoptotic function
Apoptosis is an active form of cell death that depends on new gene expression and is characterized by nuclear condensation, DNA strand breaks, cellular fragmentation, and phagocytosis by adjacent cells (Steller, 1995
). Preclinical studies suggest that chronic stress can precipitate cell death in stress-sensitive hippocampal neurons (Magarinos et al., 1996
). In addition, clinical studies have found cell atrophy and death in the hippocampus and PFC of depressed patients (Duman et al., 1999
); the hypersecretion of glucocorticoids during stress may contribute to this cell death (Lee et al., 2002
). Therefore, enhancing cell survival mechanisms that oppose these stress-induced changes could serve as a novel therapeutic approach to treating BPD.
Bcl-2 protein is a key regulator of apoptosis through its interaction with mitochondria-altering members of the Bcl-2 family. As noted previously, Bcl-2 is regulated by both lithium and valproate (Chen et al., 1999
) in addition to antidepressants (Murray and Hutson, 2007
). Animal studies have demonstrated several key findings: Bcl-2 knockout mice: 1) have altered oxidative metabolism and antioxidant levels in kidney, liver, and brain (Hochman et al., 2000
); 2) exhibit increased levels of anxiety (Einat et al., 2005
); 3) show an altered response to amphetamine, resembling the clinical phenomena found in euthymic patients with BPD treated with amphetamine (Chen et al., unpublished data); and 4) have an increased tendency to be helpless and have slower spontaneous recovery in learned helplessness tasks (Chen et al, unpublished data). Clinical studies further implicate lower Bcl-2 levels as a risk factor for BPD. For instance, Bcl-2 protein levels were found to be increased in lymphocytes from lithium-treated patients with BPD. In addition, a SNP of BCL-2 was associated with increased risk for BPD; this risk allele was also associated with the lowest Bcl-2 mRNA and protein levels, and enhanced cell death to elevated calcium levels in lymphoblast cells (Chen et al, unpublished data).
Similarly, BAG-1 appears to enhance the anti-apoptotic properties of Bcl-2 through direct interaction (), although BAG-1 shares no sequence homology with Bcl-2 family's conserved domains (Takayama et al., 1995
). BAG-1 does have sequence similarity with several ubiquitin and ubiquitin-like proteins, and some researchers have speculated that BAG-1 may orchestrate the interaction between Bcl-2 and proteosome complexes that participate in cell death regulation (Alberti et al., 2003
). As with Bcl-2, animal studies investigating the function of BAG-1 in affective resilience offer further evidence for this factor's potential as a therapeutic target for BPD (Maeng et al., 2008
2.3. Neurotrophic/neuroprotective effects
Chronic treatment with lithium and valproate activate the neurotrophic/neuroprotective signaling pathways highlighted in , including the BDNF/extracellular signal regulated kinase (ERK) pathway, the PI3K/AKT pathway, and the glycogen synthase kinase 3 (GSK-3) pathway (Shaltiel et al., 2007
). Therefore, targeting neurotrophic signaling cascades has been suggested as a putative treatment for BPD.
For example, lithium and valproate both increase BDNF in the rat frontal cortex (Einat et al., 2003
; Fukumoto et al., 2001
). BDNF, in turn, has been implicated in enhancing synaptic plasticity, cell survival, and antidepressant actions when infused directly into the hippocampus in rodent models used to screen for antidepressant efficacy (Shirayama et al., 2002
). Interestingly, lithium and valproate both protect against oxidative stress (Lai et al., 2006
), but lithium also has neuroprotective properties in a rodent cerebral ischemic model (Bian et al., 2007
). Lithium also increases brain N-acetylaspartate (NAA) concentrations (Moore et al., 2000
), a marker of neuronal viability. BAG-1 has also been shown to activate the ERK mitogen-activated protein (MAP) kinase cascades (Kermer et al., 2002
), which are key signaling cascades upstream of BDNF. Taken together, this evidence suggests that the neuroprotective effects of mood stabilizers may in part be mediated through enhancement of BDNF/ERK signaling.
2.4. Glucocorticoid/HPA axis regulation
GR signaling provides a negative feedback mechanism for the HPA axis. GRs have a lower affinity than mineralocorticoid receptors (MRs) so they are activated at higher levels of cortisol, such as during a stress response. Interestingly, very recent data support the notion that GRs can modulate mitochondrial function (specifically, mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity) by forming an association with Bcl-2 and translocating to the mitochondria to enhance neuroprotection (Du et al., in press
). By enhancing mitochondrial calcium buffering, GR in concert with Bcl-2 may increase cell survival mechanisms and reduce cell death following prolonged exposure to cytotoxic calcium levels (). Thus, GR signaling appears to play a multifaceted role, including acting not only as a negative modulator of the HPA axis, but also interacting directly with Bcl-2 to provide neuroprotection.
In animal models, overexpression of GRs in mouse forebrain leads to increased anxiety-like and depressive-like behaviors, increased sensitivity to antidepressants, and enhanced cocaine sensitization (Wei et al., 2004
). In addition, overexpression of GRs in mouse forebrain leads to mild cognitive dysfunction as well as an initial blunted response to stress followed by a delay in turning off the stress response. Wei et al. (2007)
also found that overexpression of GRs—even in the absence of stress—alters hippocampal molecular signaling, especially glutamate signaling, in addition to impairing hippocampal spatial memory tasks in the Morris water maze (Wei et al., 2007
BAG-1 is a Hsp70/Hcs70-regulating co-chaperone protein that can interact with GRs () and attenuate their nuclear trafficking and function (Schneikert et al., 1999
). Interestingly, glucocorticoids are one of the few agents that can promote either depressive or manic episodes in patients with BPD. BAG-1 overexpressing mice showed faster recovery in the amphetamine-induced hyperlocomotion test, as well as resistance to cocaine-induced behavioral sensitization (Maeng et al., 2008
); these two animal models are used to screen potential anti-manic agents. Lithium-treated animals also showed similar behavioral responses as BAG-1 overexpressing mice. Reduction of BAG-1 in heterozygous knockout mice had the opposite effect, leading to enhanced response to cocaine-induced behavioral sensitization (Maeng et al., 2008
). In terms of anxiety and depression, BAG-1 overexpressing mice demonstrated a less anxious behavioral phenotype in the elevated plus maze test and had facilitated spontaneous recovery rates from helplessness behavior compared with wild-type littermates (Maeng et al., 2008
). Small interfering RNA (siRNA) studies found that BAG-1 blocked the lithium-induced attenuation of GR activity, suggesting that mood stabilizers may be acting via BAG-1 (Zhou et al., 2005
), and lending further support to the notion that BAG-1 may be a future therapeutic target in developing novel medications for BPD.
FKBP5 also modulates GR function through its association with Hsp-90. Hsp-90 is a molecular chaperone with a central role in steroid hormone signaling. In animal studies, squirrel monkeys have high levels of cortisol, and normal expression of GR. They also possess an ortholog of FKBP5 (FKBP51). FKBP51 effectively lowers the corticosteroid binding affinity of the GR in squirrel monkeys by 11-fold and, interestingly, is expressed 13-fold higher in squirrel monkeys than in humans (Reynolds et al., 1999
). This study indicates one mechanism whereby a GR chaperone can lead to glucocorticoid resistance. Taken together, the evidence suggests that BAG-1, FKBP5, and Hsp-90 support the GR network by enhancing its function during stress-induced events by increasing negative feedback to the HPA axis or promoting cell survival mechanisms. In this manner, these modulators of glucocorticoid receptors provide another layer of control that enables GRs to have such diverse functions in regulation and survival.