The role of BDNF as a mediator of neuroplasticity in bipolar disorder

Abstract

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.

Keywords: Bipolar disorder; Brain-derived neurotrophic factor; Neuroplasticity; Neurotrophins; Stress.

Figure 1

BDNF synthesis and release from neurons. a: BDNF gene: promoters, exons and introns. The BDNF gene expression may be modulated by epigenetic mechanisms. Trauma can induce methylation of the promoters of the BDNF gene and therefore inhibit their transcription. b: Different mRNA transcripts can be produced depending on which of the promoters is activated. c: An alternative splicing mechanism removes the introns out and leads to the formation of a processed mRNA molecule ready to be translated. d: The mRNA molecule translocates out of the nucleus into the cytoplasm and is translated into proBDNF in the endoplasmic reticulum. e: The newly synthesized proBDNF heads to the Golgi apparatus and is then cleaved into mature BDNF by endoproteases. f: BDNF-containing vesicles merge to the cell membrane in a Ca²⁺-dependent way and release BDNF to the extracellular space.

Figure 2

BDNF-activated transduction pathways induce dendritic sprouting. a: BDNF binds to tyrosine kinase receptor type-B and induces the dimerization of the receptor. b: Binding of BDNF induces TrkB autophosphorylation at specific tyrosine residues of the receptor and thus creates binding sites for specific proteins. c: Three main intracellular signalling cascades are activated by TrkB: Ras-mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and the PLCg-Ca²⁺ pathway. d: Activation of PLC-g leads to the release of calcium from the endoplasmic reticulum and to activation of a calcium-calmodulin-dependent kinase II (CAMKII), ending in phosphorylation of CREB and activation of transcription. Activation of the MAPK pathway can also regulate transcription through phosphorylation of CREB. e: Signaling pathways mediate BDNF-promoted modifications of dendritic morphology. Simultaneous triggering of the PI3K and MAPK pathways concurrently alters both actin and microtubule dynamics and changes downstream dendrite branching.