Impact of the BDNF Val66Met Polymorphism on Cognition

Dincheva, Iva; Glatt, Charles E.; Lee, Francis S.

doi:10.1177/1073858411431646

Cited by 113 publications

(91 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Next, we evaluated the occurrence of this window of epigenetic plasticity also in the humanized mouse model of BDNF loss-of-function (BDNFVal66Met). The Val66Met SNP is carried by 33% of the human population and has been associated with the development of neuropsychiatric disorders (21,22). Here, we found that a subset of naive heterozygous BDNFVal66Met mice, identified at the light-dark screening method as particularly anxiety-prone (2) (Fig.…”

Section: P300 Regulates the Mglu2-driven Window Of Plasticity Opened mentioning

confidence: 73%

See 1 more Smart Citation

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Nasca

Zelli

Bigio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

View full text Add to dashboard Cite

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety-and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up-and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up-and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.S tress effects on higher brain regions, such as hippocampus, are known to involve actions of excitatory amino acids to induce structural and functional changes depending upon the type, intensity, and duration of the stressor (1). These differential responses, including determining susceptibility versus resilience to stress, contribute to the pathophysiology of debilitating stress-related disorders (2-5). The hippocampus is a brain region noted for its plasticity in response to stress and sensitivity to adrenal steroid hormones (6). Acute stress enhances synaptic plasticity that is associated with improved cognition and other adaptive functions whereas chronic stress produces opposite effects mediating, in the hippocampus, spine synapse turnover, dendritic shrinkage, impaired long-term potentiation (LTP), and suppression of adult neurogenesis in the dentate gyrus (DG) (1, 7). Importantly, neuroanatomical changes in response to repeated stress recover in young adult animals, based upon the restoration of dendritic length and branching and spine density (8). However, there are underlying changes that can be seen at the level of gene expression and epigenetic regulation that indicate that the brain is continually changing (9, 10). Epigenetic modifications, such as acetylation of histones, have also been involved in the consolidation of contextual memories that allow the brain to respond and adapt to changes in ...

show abstract

Section: P300 Regulates the Mglu2-driven Window Of Plasticity Opened mentioning

confidence: 73%

“…From a translational standpoint, BDNF signaling is also relevant. For example, 33% of the human population present a BDNF Val66Met SNP that leads to a valine-to-methionine substitution in the BDNF protein at codon 66, and this SNP has been associated with increased susceptibility to development of stress-related disorders (21,22). …”

mentioning

confidence: 99%

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Nasca

Zelli

Bigio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

View full text Add to dashboard Cite

show abstract

“…A growing body of evidence demonstrates that BDNF is involved in the pathophysiology and treatment of depression as well as in learning and memory (Dincheva et al 2012;Krishnan and Nestler 2008). Clinical data showed that in individuals with depression, BDNF was reduced in the hippocampus, and antidepressant treatment normalized the BDNF expression (Autry and Monteggia 2012).…”

Section: Discussionmentioning

confidence: 99%

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats

Xie

Laudon

et al. 2016

Psychopharmacology

View full text Add to dashboard Cite

show abstract

“…Since being established as a functional variant, the Val66Met polymorphism has been implicated as a modifier of neurocognitive function. 5 Memory performance was the first cognitive domain to be extensively screened for the effects of the Val66Met polymorphism, and while several types of memory impairments have been associated with the mutant 66Met allele in both humans 5 and mice, 20,39 episodic memory 3,40,41 has been shown to be particularly affected by restricted activity-dependent secretion of BDNF. Translating cognitive performance to brain structure and function, the effects of the Val66Met on hippocampal function and morphology has been the topic of much investigation.…”

Section: Human Neuroscience Of the Val66met Polymorphismmentioning

confidence: 99%

“…3 Genetic association studies have shown that the Val66Met polymorphism may be a risk factor for the development of neuropsychiatric disorders, 4 and that there is evidence that the polymorphism modulates aspects of neurocognitive function in otherwise healthy adults. 5 Since 2003, the year in which the Val66Met polymorphism was first described as a functional variant, 3 the number of studies evaluating the effects of this evolutionarily recent genetic aberration has progressively increased ( Figure 1). The pace of publication on BDNF and the Val66Met polymorphism has produced a gap in knowledge integration both between and within fields interested in the functional effects of this variant and the trophic effects of BDNF in its wild-type form.…”

Section: Introductionmentioning

confidence: 99%

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

2015

View full text Add to dashboard Cite

Brain-derived neurotrophic factor (BDNF) has a primary role in neuronal development, differentiation and plasticity in both the developing and adult brain. A single-nucleotide polymorphism in the proregion of BDNF, termed the Val66Met polymorphism, results in deficient subcellular translocation and activity-dependent secretion of BDNF, and has been associated with impaired neurocognitive function in healthy adults and in the incidence and clinical features of several psychiatric disorders. Research investigating the Val66Met polymorphism has increased markedly in the past decade, and a gap in integration exists between and within academic subfields interested in the effects of this variant. Here we comprehensively review the role and relevance of the Val66Met polymorphism in psychiatric disorders, with emphasis on suicidal behavior and anxiety, eating, mood and psychotic disorders. The cognitive and molecular neuroscience of the Val66Met polymorphism is also concisely reviewed to illustrate the effects of this genetic variant in healthy controls, and is complemented by a commentary on the behavioral neuroscience of BDNF and the Val66Met polymorphism where relevant to specific disorders. Lastly, a number of controversies and unresolved issues, including small effect sizes, sampling of allele inheritance but not genotype and putative ethnicity-specific effects of the Val66Met polymorphism, are also discussed to direct future research.

show abstract

Impact of the BDNF Val66Met Polymorphism on Cognition

Cited by 113 publications

References 55 publications

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

Contact Info

Product

Resources

About