Trends in Neurosciences
OpinionMolecular neurobiology of bipolar disorder: a disease of ‘mood-stabilizing neurons’?
Introduction
Bipolar disorder is characterized by recurrent episodes of mania and depression. Manic episode is characterized by elated mood, grandiosity, pressure to keep talking, flight of ideas, hyperactivity and diminished need for sleep. On the contrary, depressive episode is characterized by depressed mood, loss of interest, appetite loss, sleep disturbance, psychomotor retardation, feelings of worthlessness and suicidal ideation. Bipolar disorder severely disturbs the quality of life as a result of behavioral problems during manic episodes and difficulty in continuing work during depressive episodes, and threatens life by suicide. A milder form of manic episode is called hypomania. One manic episode is enough to diagnose bipolar I disorder, whereas at least one hypomanic episode and one depressive episode is required to diagnose bipolar II disorder. Lifetime prevalence is estimated as ∼0.8% and can be higher when bipolar II disorder is included [1]. Lithium and other mood-stabilizing agents such as valproate, carbamazepine, lamotrigine and atypical antipsychotics are effective for prevention of relapse in many but not all patients. Because lithium, the first-choice drug, has many side effects and some patients do not respond to maintenance treatment by currently available drugs, development of newer mood stabilizers would be expected.
In this review, I at first focus on the most replicated findings in biological studies of bipolar disorder reported by ten or more papers and replicated in most of them. Next, I summarize the implications from pharmacological studies such as a role of dopamine and neuroprotective effects of mood stabilizers. Based on these established findings, I introduce a theory that bipolar disorder is a disease of vulnerability at the cellular level. Next, I introduce several possible mechanisms to account for such cellular vulnerability. Finally, I propose a new hypothesis that bipolar disorder might be caused by progressive impairment of mood-stabilizing neurons.
Section snippets
Established biological findings in bipolar disorder
To date, numerous studies on the biology of bipolar disorder have been published. Among the literature, the most established finding is the role of genetic factors in bipolar disorder as evidenced by twin studies. All 11 published twin studies showed a higher concordance of bipolar disorder in monozygotic twins than in dizygotic twins [1]. This finding clearly indicates the role of genetic factors. Some of these genetic factors might be common to schizophrenia. In the last two decades,
The role of dopamine
Several lines of pharmacological evidence support the role of dopamine in mania and depression. Antipsychotics having antimanic efficacy block dopamine neurotransmission. Psychostimulants that increase dopamine neurotransmission cause mania. Tricyclic antidepressants (TCA) can cause an abrupt transition from depression into mania. This phenomenon, called manic switch, is not a general side effect of TCA, but is regarded as a sign of genetic vulnerability to bipolar disorder. Selective serotonin
Mechanism of clinical action of mood stabilizers
The molecular mechanism of the clinical action of mood stabilizers has been extensively studied. The most accepted hypothesis of lithium's effect is intracellular depletion of inositol by inositol-monophosphatase (IMPase) inhibition [20]. Since the studies by Nonaka et al.[21] and Chen et al.[22], which revealed neuroprotective effects of lithium and valproate, the hypothesis that mood stabilizers exert their therapeutic effects through their neuroprotective effect has been widely accepted.
Vulnerability of neurons?
Among the established findings in bipolar disorder, SCH is a nonspecific finding that is also seen in healthy subjects. Because bipolar disorder has no characteristic specific location of the lesion, increased incidence of SCH might reflect the vulnerability of neurons to cellular stress. It is also possible that this reflects vulnerability of oligodendrocytes, because reduced myelin staining [35] and decreased expression of oligodendrocyte-related genes [36] were reported in the postmortem
Molecular basis of vulnerability at the cellular level
What is the molecular basis of vulnerability or impaired resilience of neurons in patients with bipolar disorder? Impaired calcium signaling, altered neurotrophin signaling, mitochondrial dysfunction and endoplasmic reticulum (ER) stress response dysfunction might be relevant. These pathways are closely related: neurotrophins regulate intracellular calcium signaling, and mitochondria and ER coordinately play important roles in regulation of store-operated calcium channels and intracellular
Calcium channels
Agonist-induced calcium influx by thrombin, serotonin and platelet activating factor is reportedly enhanced in the cells derived from patients with bipolar disorder regardless of the agonist used 8, 49. Warsh and colleagues [49] have studied the molecular basis of altered calcium signaling in bipolar disorder using lymphoblastoid cells derived from patients. Response to thapsigargin, an inhibitor of the ER Ca2+ pump, was also enhanced in peripheral blood cells from patients with bipolar
Phosphoinositide pathway
As noted above, the phosphatidylinositol pathway is a potential target of lithium. Phosphatidylinositol bisphosphate is hydrolyzed into inositol triphosphates (IP3) and diacylglycerol. IP3 releases calcium from the ER.
Decreased levels of inositol [53], reduction of inositol monophosphatase 2 (IMPA2) mRNA 54, 55 and reduced activity of IMPase [56] were reported in lymphoblastoid cells or lymphocytes derived from patients with bipolar disorder. Genetic factors might contribute to altered inositol
Glycogen synthase kinase 3β
GSK-3β plays a role in various intracellular signaling, including neurotrophin and Wnt signaling pathways. GSK-3β is regulated by intracellular calcium signaling. Because mood stabilizers inhibit GSK-3β 27, 28, a role for this pathway in bipolar disorder is suggested.
In addition to a role in cellular vulnerability, GSK-3β is also suggested to play a role in abnormality of the circadian rhythm in bipolar disorder [64]. Overexpression of GSK-3β shortens the circadian period [65], and lithium
Mitochondrial dysfunction
Magnetic resonance spectroscopy (MRS) findings suggested that patients with bipolar disorder had altered energy metabolism in the brain such as decreased phosphocreatine [69] and intracellular pH [70], increased lactate [71] and reduced creatine 72, 73, 74. These MRS findings resembled those in mitochondrial diseases such as chronic external ophthalmoplegia (CPEO), which is caused by multiple deletions of mitochondrial DNA (mtDNA) in muscles. A pioneering work by Suomalainen et al.[75] showed
Endoplasmic reticulum stress dysfunction
In a comprehensive gene expression analysis of lymphoblastoid cells derived from two pairs of monozygotic twins discordant for bipolar disorder, two genes related to ER stress response were commonly downregulated in the patients [92]. X-box-binding protein 1 (XBP1) is a basic leucine zipper transcription factor important for the development of liver [93] and plasma cells [94]. XBP1 mRNA undergoes unconventional splicing by IRE1 on the ER membrane when unfolded proteins accumulate in the ER [95]
Disease specificity of the proposed pathogenesis
In this manuscript, the nature of this cellular vulnerability in bipolar disorder and its implication in the neurobiology of this disease are reviewed. However, cellular vulnerability is not a specific risk factor for bipolar disorder. In particular, mitochondrial dysfunction and dysfunctional ER stress response have been suggested in other diseases such as Parkinson's disease and diabetes mellitus 106, 107. POLG mutations confer the risk of both diseases [108], and mutations of XBP1 [109] and
Mood-stabilizing neuron hypothesis
In bipolar disorder, the episode interval is shortened with the progression of the illness, and patients develop vulnerability to stress. When patients manifest rapid cycling, lithium is no longer effective. This characteristic course of the illness has been explained by kindling or behavioral sensitization [110], but might also be well explained by the progressive loss or dysfunction of the neurons responsible for mood stabilization. This hypothesis might be more relevant to the current
Conclusion
Genetic factors contribute to the onset of bipolar disorder, and manic and depressive episodes are accompanied by alteration of dopaminergic neurotransmission. Increased incidence of subcortical hyperintensity, altered calcium levels in platelets and neuroprotective effects of mood stabilizers altogether suggest that cellular vulnerability is implicated in bipolar disorder. Calcium channels, GSK-3β, mitochondrial dysfunction and ER stress dysfunction are suggested to play a role in such
Conflict of interest
RIKEN, which the author belongs to, has a Japanese patent (2005-124412) for the mutant POLG transgenic mouse as an animal model of bipolar disorder.
Acknowledgements
This work was supported by grants for the Laboratory for Molecular Dynamics of Mental Disorders, RIKEN BSI and grants in aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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