Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior

Abstract

A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF Met/Met ) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF Met was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.Depression and anxiety disorders have genetic predispositions, yet the particular genes that contribute to this pathology are not known. One candidate gene is BDNF, because of its established roles in neuronal survival, differentiation, and synaptic plasticity. The recent discovery of a single-nucleotide polymorphism (SNP) in the bdnf gene (Val66Met), found only in humans, leading to a Met substitution for Val at codon 66 in the prodomain, has provided a valuable tool to assess potential contributions of BDNF to affective disorders. This polymorphism is common in human populations with an allele frequency of 20 to 30% in Caucasian populations (1). This alteration in a neurotrophin gene correlates with reproducible alterations in human carriers. Humans heterozygous for the Met allele have smaller hippocampal volumes (2-4) and perform poorly on hippocampal-dependent memory tasks (5,6). However, in genetic association studies for depression and anxiety disorders, there is little consensus as to whether this allele confers susceptibility.The mechanisms that contribute to altered BDNF Met function have been studied in neuronal culture systems. The distribution of BDNF Met to neuronal dendrites and its activity-dependent secretion are decreased (6-8). These trafficking abnormalities are likely to reflect impaired binding of BDNF Met to a sorting protein, sortilin, which interacts with BDNF in the prodomain †To whom correspondence should be addressed.

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Moreover, it is important to note that antidepressants are used to treat many different psychiatric conditions, including a variety of anxiety disorders. Indeed, another more specific BDNF mutant mouse where the 66th amino acid, valine, is converted into methionine (Val66Met knock-in mice) exhibit increased anxiety-related behaviors (Chen et al, 2006). Treatment with the antidepressant fluoxetine was unable to reverse behavioral anxiety in the Val66Met knockin mice, suggesting BDNF as a downstream target for the anxiolytic effects of selective serotonin reuptake inhibitors (SSRI) (Chen et al, 2006).…”

The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model

“…Biological plausibility for the present research resides in the joint effect of BDNF Val66Met and parenting on abnormal BDNF functioning, which has been shown to be involved in depression (Castrén and Rantamäki 2010). Specifically, the Val66Met polymorphism has been shown to reduce intracellular trafficking and activity-dependent secretion of BDNF (Chen et al 2006;Egan et al 2003;Kuczewski et al 2009). Rodent studies indicate that maternal behavior including postnatal maternal separation (negative) and higher quality maternal care (positive) can influence offspring's BDNF expression in brain (Bath et al 2013;Cutuli et al 2015;Mashoodh et al 2012).…”

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample

“…Previous studies have found associations between the Met66 allele and increased introversion (Terracciano et al, 2010), harm avoidance (Montag, Basten, Stelzel, Fiebach, & Reuter, 2010), tendency to ruminate (Beevers, Wells, & McGeary, 2009), lower levels of conscientiousness (Hiio et al, 2011), an increased vulnerability to stress (Casey et al, 2009), increased anxiety-related behaviours (Chen et al, 2006) and increased risk of an anxiety disorder in children and adolescents (Tocchetto et al, 2011). In contrast, other studies have reported an association between the Val66 allele and higher neuroticism scores, as well as increased risk of anxiety symptoms during adolescence (Chen, Yu, Liu, Zhang, & Zhang, 2015; Frustaci et al, 2008).…”

“…Brain-derived neurotrophic factor (BDNF) is a secretory protein in the neurotrophin family known to influence the proliferation, survival, differentiation, repair and regulation of synaptic plasticity of neuronal cells in the developing and adult brain (Bath & Lee, 2006; Chen et al, 2006; Martinowich, Manji, & Lu, 2007; Notaras, Hill, & van den Buuse, 2015). BDNF is widely expressed in the hippocampus and cerebral cortex (Hofer, Pagliusi, Hohn, Leibrock, & Barde, 1990; Huang & Reichardt, 2001) and enhances hippocampal long-term potentiation (Figurov, Pozzo-Miller, Olafsson, Wang, & Lu, 1996) associated with both memory and learning efficiency (Hariri et al, 2003; Yamada, Mizuno, & Nabeshima, 2002).…”

“…military training, psychological job stress, acute and repeated restraint in animals) are associated with decreased BDNF (Mitoma et al, 2008; Murakami, Imbe, Morikawa, Kubo, & Senba, 2005; Suzuki et al, 2014) and enhancement of anxiety-related behaviours (Chen et al, 2006). In adults with lifetime major depressive disorder, for example, a linear relationship between exposure to CM (i.e.…”