Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder

Abstract

Objective: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3.

Methods: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.'

Results: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes.

Conclusion: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.

© 2012 John Wiley & Sons A/S.

Figures

Fig. 1

Signaling abnormalities and impairment of neurotrophic cascades that underlie the neurobiological basis of bipolar disorder. Lithium increases their expression and/or levels, thus inducing neuroprotective and neurotrophic effects. Activation of brain neurotransmitter-coupled G-proteins induces PLC hydrolysis of PIP2 to IP3 and DAG (not shown), which activates PKC. IP3 binds to the IP3R, thus inducing the release of ER calcium stores. Elevated intracellular calcium levels have been described in bipolar disorder and may increase the risk of apoptosis. The neuroprotective protein Bcl-2 downregulates ER calcium release through an IP3R–dependent mechanism. The same effect is induced by lithium treatment, which also increases Bcl-2 levels. IP3 is recycled by IMPase, another of lithium’s targets. Cellular signaling through Wnt glycoproteins and frizzled receptors result in GSK-3β inhibition, a critical cellular target and effector for diverse proteins. Inhibition of GSK-3β prevents β-catenin phosphorylation and stimulates its translocation to the nucleus, thus targeting transcription of specific genes activating neurotrophic effects and synaptogenesis. Activation of the BDNF receptor (Trk-B) activates the ERK/MAPK pathway, which inhibits GSK-3β and BAD. Activation of the extracellular signal-regulated kinase-mitogen- activated protein kinase pathway by BDNF increases the expression of nuclear CREB, which facilitates the expression of neurotrophic/neuroprotective proteins such as Bcl-2 and BDNF. BDNF also activates the PI3K pathway, which indirectly inhibits GSK-3β and BAD. Mitochondrial Bcl-2 and Bcl-xl also inhibit pro-apoptotic activation of BAD, as well as consequent mitochondrial increase in calcium influx and cytochrome C release. Bcl-2 = B-cell lymphoma-2; BDNF = brain-derived neurotrophic factor; CREB = cAMP response element binding protein; DAG = diacylglycerol; ERK = extracellular regulated kinase; GSK = glycogen synthase kinase; IMPase = inositol monophosphatase; IP3 = inositol 1,4,5-triphosphate 3; PI3K = phosphatidylinositol-3 kinase; PIP2 = phosphoinositide 4,5-biphosphate; PKC = protein kinase C; PLC = phospholipase C; PTP = permeability membrane pore; TrkB = tyrosine receptor kinase B; RAS= RAt Sarcoma; AKT = B; PLA2 = Phospholipase A2; PLC= Phospholipase C; VEFG = Vascular endothelial growth factor; NT-3 = Neurotrophin-3.