Cellular mechanisms underlying affective resiliency: The role of glucocorticoid receptor- and mitochondrially-mediated plasticity

Abstract

Bipolar disorder (BPD) is a devastating psychiatric illness marked by recurrent episodes of mania and depression. While the underlying pathophysiology of BPD remains elusive, an abnormal hypothalamic–pituitary–adrenal (HPA) axis and dysfunctional glucocorticoid receptor (GR) signaling are considered hallmarks. This review will examine how targeting resiliency signaling cascades at the cellular level may serve as a mechanism to treat BPD. Here, cellular resiliency is defined as the ability of a cell to adapt to an insult or stressor. Such resiliency at the cellular level could confer resiliency at the systems level and, ultimately, help individuals to cope with stressors or recover from depressive or manic states. This review will focus on four molecular targets of mood stabilizers that are known to play integral roles in these cellular resiliency signaling pathways: (1) B-cell CLL/lymphoma 2 (Bcl-2), (2) Bcl-2-associated athanogene (BAG-1), (3) glucocorticoid receptors (GRs), and (4) 51 kDa FK506-binding protein (FKBP5). These targets have emerged from neurobiological and human genetic studies and employ mechanisms that modulate GR function or promote anti-apoptotic processes critical to affective resilience. Future research should focus on elucidating sustainable treatments that target resiliency factors—such as BAG-1 or FKBP5—which could ultimately be used to treat individuals suffering from BPD and prevent relapses in afflicted individuals. Further identification of resiliency and susceptibility factors will also be vital. Ultimately, these developments would allow for the treatment of susceptible individuals prior to the development of BPD.

Introduction

Bipolar disorder (BPD) is a common, severe, chronic, and sometimes life-threatening illness that places an enormous economic and emotional burden on society in addition to the patients and families directly affected (Goodwin and Jamison, 2007). The disease is characterized by recurrent episodes of mania and depression. A variety of pharmacological therapies are available to treat BPD; for acute manic episodes and its subtypes, these options consist mainly of lithium, anticonvulsants (e.g., valproate), and both typical and atypical antipsychotic agents (Baldessarini et al., 2003, Tohen et al., 2001, Zarate and Tohen, 2000). However, for most patients with BPD, monotherapy is often insufficient and combination treatment is required (Zarate and Quiroz, 2003). Furthermore, it has become apparent in recent years that these options are far from adequate in treating recurrences, relapses, and acute episodes of the illness in addition to restoring premorbid functioning. For long-term prophylaxis, far fewer agents are available; they include lithium, aripiprazole, and lamotrigine, but of these only lamotrigine has been shown to help prevent depressive relapses (McElroy et al., 2004). In addition, some patients are unable to tolerate existing therapies for BPD, which leads to frequent changes in medications or non-adherence (Sajatovic et al., 2006, Zarate et al., 1999, Zarate and Tohen, 2004). Thus, currently available therapies for BPD are insufficient, and demand the development of new therapeutics that are more effective and better tolerated.

One possible avenue for the development of novel therapies may come from studying the mechanisms of affective resilience. This review will consider some of the cellular substrates that are thought to underlie this phenomenon. While most of our discussion will examine cellular resiliency pathways with a focus on anti-apoptotic, glucocorticoid, and neurotrophic signaling cascades, it is important to acknowledge that other pathways involving biogenic amines, glutamate, etc. also play important roles in this disease (interested readers, see Manji et al. (2003)). This review, however, will focus on recent developments that support the role for specific glucocorticoid receptor (GR)-related proteins and B-cell CLL/lymphoma 2 (Bcl-2) family members as resiliency factors in BPD.

While the etiology of BPD is unknown, a variety of environmental and genetic factors have been implicated. For instance, family, twin and adoption studies have revealed a familial aggregation of BPD—there is a ten-fold higher risk for the disorder in individuals with an affected first-degree relative compared to individuals with unaffected first-degree relatives (Smoller and Finn, 2003). While it is still challenging to quantitatively assign the heritability of BPD, many studies support the hypothesis that a variety of genetic risk factors exist for the disease.

Broadly speaking, these genetic risk factors may lead to dysfunction of the stress response. Following an acute stressor, a multitude of biochemical and physiological changes occur. Some of these biochemical changes include release of catecholamines (epinephrine and norepinephrine) from the sympathetic nervous system. In addition to activation of the sympathetic nervous system, the hypothalamic–pituitary–adrenal (HPA) axis is also activated following stress by release of corticotropin releasing hormone (CRH) from the hypothalamus to the pituitary gland which releases adrenocorticotrophic hormone (ACTH) that activates the adrenal gland's release of glucocorticoids. In turn, these biochemical signals initiate a host of physiological changes ranging from enhanced mobilization of energy stores to muscles, increased cardiovascular tone, and cognitive function while decreased digestion, immune function, growth, and reproduction (for a more complete review see Sapolsky et al. (2000)).

Problems arise when this system is unable to turn off, which can occur during chronic stress. GR signaling provides an important negative feedback loop to the HPA axis' regulation of the stress response. Dysfunctional GR activity (either hypersensitivity or resistance to glucocorticoids) may contribute toward hyperactivation of the HPA axis, which is one of the most consistent biological disruptions noted in patients with depression.

Patient-based studies have shown that genetic components of the GR signaling pathway may contribute to some individuals' predisposition to mood disorders or to the efficacy of certain medications. Genetic studies looking at single nucleotide polymorphisms (SNPs), single base pair changes in a DNA nucleotide sequence that often influences a gene's activity and expression, in the GR gene have implicated this gene as a risk factor for major depressive disorder (MDD). Van West et al. analyzed SNPs in the GR gene (Nuclear Receptor Subfamily 3, Group C Member 1; NR3C1) and discovered that polymorphisms in the 5′ region of the NR3C1 gene conferred genetic risk for MDD (van West et al., 2006). Further research is required to perform functional studies that will look at how SNPs influence GR expression and function.

Another group looked at different polymorphisms in the GR gene. These polymorphisms had functional changes in the GR gene by either being associated with hypersensitivity (BclI, polymporphism in the BclI restriction site in intron 2 and a C to G nucleotide change 646 base pairs downstream from exon 2) or resistance (ER22/23EK, polymorphism in exon 2 consisting of 2 linked nucleotide changes in codons 22 and 23 GAG AGG → GAA AAG where the first nucleotide change in codon 22 is silent, coding for glutamic acid, E, and the second change arginine, R, to lysine, K) to glucocorticoids. Interestingly, this group found an increased risk of depression in homozygous carriers of BclI and certain ER22/23EK polymorphisms, due to glucocorticoid hypersensitivity or resistance within these respective genotypes (van Rossum et al., 2006). This study supports the concept that GR signaling dysfunction can lead to depression through either glucocorticoid hypersensitivity or resistance. Yet simple increases or decreases in GR expression cannot be attributable to either dysfunction or enhanced function. Furthermore, the ER22/23EK carriers had a faster response to antidepressants, suggesting that in the future, genetics may be used to predict a patient's therapeutic response to treatments dependant upon glucocorticoid hypersensitivity or resistance.

Additional biochemical studies have found that GR function (measured as the response to steroid manipulations of either GR binding and translocation to the nucleus or of peripheral cell functions) is decreased in major depression without consistently showing a concomitant decrease in GR expression. Some antidepressants improve GR function and increase its expression (reviewed in Pariante and Miller (2001)). Wassef et al. found that, following oral dexamethasone (a synthetic glucocorticoid) administration, control subjects had a suppression of GR expression while depressed patients failed to exhibit this response (Wassef et al., 1990). An additional study found that depressed patients had higher plasma cortisol concentrations relative to control patients, but they did not show any increase in the GR-responsive enzyme sialytransferases, nor were there any changes in GR binding (Maguire et al., 1997).

Mechanisms that may underlie GR dysfunction have been suggested to include: (1) downregulation of GR even with elevated cortisol levels, (2) genetic alterations in GR influencing function, and (3) ligand-independent mechanisms impacting GR function. While most studies have not shown a consistent downregulation of GR in depressed patients, the elevated cortisol levels may ultimately overburden the recycling capacity of GR and dampen its negative feedback. We have already considered several genetic polymorphisms (i.e. ER22/23EK) that may impact GR function, however, further studies are required to elucidate the exact mechanisms. In terms of ligand-independent mechanisms, factors such as proinflammatory cytokine interleukin 1 and factors involved in the cyclic adenosine monophosphate (cAMP) cascade such as protein kinase A (PKA) have both been shown to impact GR function. Miller et al. show interleukin 1 has an inhibitory effect on GR translocation and hormone-induced GR-mediated gene transcription (Miller et al., 1999). Interestingly, antidepressants have been reported to upregulate GR protein and mRNA in addition to facilitating GR translocation and enhancing HPA axis negative feedback mechanisms (reviewed in Pariante and Miller (2001)). These effects may ultimately restore GR negative feedback mechanisms in depressed patients.

GRs are modulated by a variety of factors/mechanisms including antidepressants, cytokines, and intracellular signaling cascades as mentioned above. Another important regulator is the chaperone protein 51 kDa FK506-binding protein (FKBP5). FKBP5 acts as a negative feedback regulator through its association with heat shock protein 90 (Hsp90) and p23 (see Fig. 1) of GR activity (Vermeer et al., 2003). The TT homozygous FKBP5 polymorphism has been associated with an increased number of depressive episodes in patients with various mood disorders, as well as enhanced response to antidepressant treatment (Binder et al., 2004). In addition, genetic variation within FKBP5 correlates with the number of suicide attempts and the number of depressive episodes in BPD (Willour et al., 2008). Further clinical evidence comes from Lekman et al. (2008), who found markers in FKBP5 associated with either disease status (rs1360780) or remission (rs4713916) in white, non-Hispanic patients suffering from MDD (Lekman et al., 2008).

In addition to the association between BPD and dysfunctional GR signaling, grey matter volume and glial reductions in the prefrontal cortex (PFC) have also been noted, suggesting a deficit in survival, neurotrophic, and plasticity mechanisms (Drevets et al., 1998). These deficits may be facilitated by impaired cellular function and decreased resistance to cellular insults following prolonged exposure to glucocorticoids. Very recent findings from two independent samples identified an association between BPD and a SNP in the anti-apoptotic gene BCL-2 (Chen et al, unpublished data). This BCL-2 SNP was associated with lower Bcl-2 mRNA and protein levels. Furthermore, lymphoblasts collected from probands in these families with the BCL-2 risk allele showed an increased rate of cell death in the presence of cytotoxic calcium levels. This diverse group of studies has shown that impaired GR function is correlated with a multitude of factors that influence behavior states, including reduced GR-mediated negative feedback of the HPA axis, diminished sensitivity to cortisol, impaired cell survival mechanisms, and reductions in brain area volume. In this manner, behavioral and cellular resilience can be achieved by either enhancing GR's negative feedback mechanisms or reducing prolonged exposure to glucocorticoids by enhancing survival mechanisms.