Assessment of Genetic Mechanisms of Bipolar Disease and BDNF - Research Paper Example

?BDNF and Bipolar Disorder Bipolar disease is one of the chronic mood disorders with a strong component of inheritance (Fan and Skar, 60). The lifetime incidence of this condition is estimated to be atleast 1 percent (Kapczinski, p.1101). Epidemiological studies have incriminated both environmental and biological factors in the pathophysiology of bipolar disease. Biological factors involved in the pathogenesis are impairment in the neuronal survival and synaptic plasticity which again is determined by various neurotrophins, neural hormones and neurotransmitters. Synaptic plasticity, defined as "experience-dependent change in synaptic strength" (Kapczinski, p.1101), has been considered as a significant pathologic feature in the development of bipolar disease. Research has shown that the key mediator for synaptic plasticity and other pathologic features in bipolar disease like dendritic arborization and neuronal connectivity is the brain derived neurotrophic factor or BDNF (Kapczinski, p.1101). Assessment of genetic mechanisms of bipolar disease, especially the val66val alllele and the val66met allele and various other single nucleotide polymorphisms of BDNF which are potential vulnerable factors, can facilitate and fuel studies pertaining to various early interventions for bipolar disease, thus helping reduce prolonged delay between identification of the symptoms and initiation of treatment. Such a research also helps in the prediction of the response of the individual to a particular treatment (Post, p.979). Both BDNF and its receptor, TrkB are expressed broadly in both developing and also adult brain of the mammals, including humans. Infact, it is a well known fact that binding of BDNF to TrkB is critical for several intracellular signaling pathways like phospholipase Cg (PLCg), mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and phosphoinositide 3-kinase (PI3K) pathways and throgh these pathways BDNF exerts several biological effects on the neurons (Numakawa, p.237). Regulation of mood, cognition and behaviour is mainly regulated by the networks involving the limbic system, striatum, pallidum, thalamus and cortex. Specific abnormalities related to mood disorders have been described in amygdala, hippocampus, cingulate gyrus and prefrontal cortices (Matsuo et al, p.1904). BDNF is a genomic structure that is highly complex and contains "multiple 5'-noncoding exons that are spliced to a common 3'-coding exon that encodes for the BDNF protein" (Kapczinski, p.1101) A set of complex genomic promoters control the production of BDNF accurately. There is whopping evidence to show that chromatin remodeling of BDNF gene leads to various effects of stress that are deleterious, along with a response that is antidepressant (Kapczinski, p.1101). BDNF is expressed in high quantities in the cortex, limbic structures, hippocampus, olfactory bulb and cerebellum. In these regions, the genomic structure is involved in certain basic neuronal functions like axonal outgrowth, cell survival, synaptic plasticity and dendritic growth (Matsuo et al, p.1904). There is mixed evidence about the link between polymorphic markers in BDNF gene and bipolar disorder. While two large studies by Neves-Pereira et al, 2002 and Sklar et al, 2002 have demonstrated strong association between the two, several others studies have not been able to replicate the results in their samples. Some research has also pointed to the role of this gene in childhood-onset mood disorders (Muller et al, p.317). Several animal studies have suggested association between BDNF and treatments for mood disorders like valproate, lithium, electroconvulsive therapy and magnetic stimulation which interfere with the messenger RNA of the BDNF in the frontal lobe or in the hippocampus (Matsuo et al, p.1905). According to a study by Lang et al (2007; cited in Matsuo et al, p.1904), "serum BDNF levels are positively associated with the concentration of N-acetyl aspartate, a marker of neuronal integrity, and choline, a marker of cell membrane turnover, in the anterior cingulate cortex (ACC), suggesting that peripheral BDNF content may be a potential marker of cerebral cortical integrity." Several epidemiological studies emotional trauma and stress are associated with psychopathological problems like bipolar disorder. One of the neurobiological mediator of stress related psychopathology is BDNF. This is because; BDNF is secreted through regulatory pathway mainly in response to neuronal activity unlike other neurotransmitters. There is enough evidence to suggest a role of BDNF "in experience-dependent processes during formation and plasticity of circuits in the brain" (Kapczinski et al, p.1102). Thus, stress decreases BDNF expression. Alteration of the expression of BDNF hippocampus, in relation to early stressor, including prenatal stress, leads to mood related disorders like unipolar and bipolar disorder. Several studies have demonstrated reduction in the levels of serum BDNF in acute mood episodes, thus suggesting the role of serum BDNF level estimation in the identification of activity of bipolar disease. This is further supported by the fact that BDNF levels are normal in euthymia and they rise after initiation of mood stabilisers. Of the several polymorphisms of BDNF, Val66Met polymorphism has been strongly associated with bipolar disease. In this polymorphism, position 66 in the prodomain is substituted by valine/methionine. In a large meta-analysis by Fan and Sklar (2008, p.60), there was statistically significant evidence for association between bipolar disease and Val66met polymorphism (random-effects pooled odds ratio = 1.13, 95% Confidence Interval = 1.04-1.23, Z = 2.85, P = 0.004). Some family-based studies have proved that Val66Met polymorphism is associated with bipolar disease and also the rapid cycling phenomenon. According to a study by Egan et al (2003; cited in Matsua et al, p.1905), "healthy subjects with Val/Met BDNF also receive lower scores on cognitive tasks compared with Val/Val subjects." Neuroimaging studies by researchers like Bueller et al (2006; cited in Matsua et al, p.1905) have shown that healthy individuals with Val/Met actually show lower volumes of hippocampus, parahippocampus and dorsolateral prefrontal cortex when compared to individuals withVal/Val. Among bipolar disorder population, studies have shown that Met carriers have more loss of volume in the temporal lobe regions over 4 years of time when compared to those with Val/Val. Matsua et al (p.1905) demonstrated that Val66Met polymorphism deranged levels of creatinine and also phosphocreatinine levels in the dorsolateral prefrontal cortex regions, especially the Met carrier subjects who had low levels of these chemicals, suggestive of impairment in the energy metabolism in dorsolateral prefrontal cortex in those with bipolar disease. Thus, various polymorphisms of the genomic structure BDNF in specific regions of the brain related to emotion, cognition, and behaviour contribute to bipolar disease and this is evident from various neuroimaging, serum, epidemiological and family studies. Work Cited Page Fan J, Sklar P. “Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism.” Novartis Found Symp. 2008;289:60-72 Kapczinski, F., Frey, BN, Anna, MK., and Oliveira, RG. “Brain-derived neurotrophic factor and neuroplasticity in bipolar disease.” Expert Rev. Neurother 2008;:8(7), 1101- 1113. Matsuo, K., Walss-Bass, C, Nicoletti, MA., et al. “Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder.” Neuropsychopharmacology 2009, 34:1904–1913. Muller, DJ, De Luca, V, Sicard, T, King, N., Strauss, J, and Kennedy, JL. (2006). “Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder.” The British Journal of Psychiatry 2006),189: 317-323 Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H. “BDNF function and intracellular signaling in neurons.” Histol Histopathol. 2010 Feb;25(2):237-58 Post RM. “Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications.” J Psychiatr Res. 2007 Dec;41(12):979-90 Read More