BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting

BDNF stands for brain-derived neurotrophic factor, the protein generated by the BDNF gene, a substance that has been drawing a lot of attention recently in neuropsychiatric research circles.  I review some basic facts about BDNF here, recent research on how BDNF relates to personality, mental balance, and aging and, finally, current research on how BDNF expression is conditioned by epigenomic imprints.

About BDNF

“BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.^[4][5] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.^[6] BDNF itself is important for long-term memory(ref).^[7] ”  BDNF is an important neurotrophic, meaning that it plays an important role in neurogenesis, the important process in parts of the brain of neural stem cells differentiating into neurons. “Neurotrophins are a family of proteins that induce the survival,^[1] development and function^[2] of neurons. — Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. More specifically, it is a protein which has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3. — Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate(ref).”

BDNF and mental balance

According to the December 30 2009 paper BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism. “Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. — ). Consistent with GWA results, we found that BDNF Met carriers were more introverted. — Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.” 

Also, aberrant BDNF is implicated in memory loss, anxiety and schizophrenia. Again, the culprit gene variant seems to be Val66met.  According to the 2008 publication Impact of genetic variant BDNF (Val66Met) on brain structure and function, “A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) — A genetic variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.”   Another relevant 2008 research publication is Meta-Analysis of the Brain-Derived Neurotrophic Factor (BDNF} Val66Met Polymorphism in Anxiety Disorders and Anxiety-Related Personality Traits.

Research study after research study have pointed to the importance of healthy expression of BDNF for long term memory including BDNF: A Key Regulator for Protein-synthesis Dependent LTP and Long-term Memory? and Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF.

The association of BDNF VAL66Met with mental issues has been known for several years now.  According to the 2005 publication Association of a functional BDNF polymorphism and anxiety-related personality traits “Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. — Our findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.”

Going back even a bit further, according to a 2003 NIMH research press release “NIH scientists have shown that a common gene variant influences memory for events in humans by altering a growth factor in the brain’s memory hub. On average, people with a particular version of the gene that codes for brain derived neurotrophic factor (BDNF) performed worse on tests of episodic memory—tasks like recalling what happened yesterday. They also showed differences in activation of the hippocampus, a brain area known to mediate memory, and signs of decreased neuronal health and interconnections. These effects are likely traceable to limited movement and secretion of BDNF within cells, according to the study, which reveals how a gene affects the normal range of human memory, and confirms that BDNF affects human hippocampal function much as it does animals'(ref).” 

The BDNF dementia and aging connection

Expression of BDNF is implicated in aging.  The 2008 study report Genetic contributions to age-related decline in executive function: a 10-year longitudinal study of COMT and BDNF polymorphisms says “Our results argue that — the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age.”

In fact expression of BDNF is implicated in anti-aging.   According to a news item published yesterday “UC Irvine neurobiologists are providing the first visual evidence that learning promotes brain health – and, therefore, that mental stimulation could limit the debilitating effects of aging on memory and the mind. Using a novel visualization technique they devised to study memory, a research team led by Lulu Chen and Christine Gall found that everyday forms of learning animate neuron receptors that help keep brain cells functioning at optimum levels. — These receptors are activated by a protein called brain-derived neurotrophic factor, which facilitates the growth and differentiation of the connections, or synapses, responsible for communication among neurons. BDNF is key in the formation of memories.” — “The findings confirm a critical relationship between learning and brain growth and point to ways we can amplify that relationship through possible future treatments,” says Chen, a graduate researcher in anatomy & neurobiology.”  I have reported previously in this blog on the importance of mental exercise and learning for prevention of dementia and longevity.  See the blog posts Mental exercise and dementia in the news again and Brain fitness, Google and comprehending longevity.  The new finding highlights the key role of BDNF expression in the process. 

I mentioned research on the use of neural stem cells as a source of BDNF in the blog entry Human embryonic stem cells and Alzheimer’s disease quoting the 2009 research report Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. “Additionally, the improvement in memory and the increase in synaptic density observed after injection of neural stem cells were found to be mediated, at least in part, by the neurotrophic factor BDNF, which is secreted from the transplanted cells. GRNOPC1 has been found to secrete BDNF as well as other neurotrophic factors(ref).”  “Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF(ref).”

The BDNF epigenetics connection – DNA methylation and chromatin remodeling

Recent studies have gone beyond looking at the Val66Met polymorphism to identifying another reason for unwanted downregulation of BDNF expression – BDNF gene promoter methylation.  The 2010 paper Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects points to downregulation of BDNF activity due to DNA methylation being observed in suicide subjects.  The paper reports: Context  Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood.  Objectives  To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.  Design  Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. ^—. Main Outcome Measures  The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain’s Wernicke area. Results  Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). —  Higher methylation degree corresponded to lower BDNF messenger RNA levels.  Conclusions  BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.”  It is tempting to hypothesize that BDNF methylation is a causal factor in suicides but the paper does not go that far.

The 2008 paper Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory reports: Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. — altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus — .  These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.”

Going back a bit earlier there was the 2005 paper Regional expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain. “These studies demonstrate that DNA methylation of this regulatory region may be an important mechanism controlling differential expression of BDNF during forebrain development.”

Early-life experiences or experiences of parents or grandparents can create changes in BDNF DNA methylation which affect learning, attitude or mental stability, as pointed out in the 2009 publication Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene.  “Background: Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. With a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the brain-derived neurotrophic factor (BDNF) gene in the central nervous system.  Methods: During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span as well as DNA methylation patterns in the next generation of infants.  Results: Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen.  Conclusions: These results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.”

Putting it together

There are many more relevant BDNF literature citations out there, but these are sufficient to make certain key points:

·        Healthy BDNF gene expression is important for mental health, learning, memory, and preservation of cognitive capability with aging

·        One thing that can get in the way of healthy BDNF gene expression is the Val66Met polymorphism in the BDNF gene, a genetic condition.

·        Another thing that can get in the way of healthy BDNF gene expression is gene methylation, a type of epigenetic modification that can be induced by experience and that is possibly inheritable.  We have all known that early experience shapes the character.  We now know that one way that shaping takes place is molecularly via methylation of the BDNF gene.

·        Certain stem cells like those in Geron’s proprietary hESC-based GRNOPC1 line secrete BDNF and offer one means for introducing BDNF expression into tissues.