The Interaction Between BDNF and Serotonin

We are truly intricate and complex  —  a biological system — and genetic variants often don’t have a huge impact on their own. Instead, the impact comes in the combination of gene variants or the interaction of a variant with the environment (toxins, stress, sleep, diet, pathogens, etc).

A brain imaging study recently showed that the combination of a BDNF genetic variant plus a serotonin receptor variant literally changes the brain. Instead of just looking at a single genetic variant, this article digs into how the combination of these two variants interact to increase the risk of depression, anxiety, and bipolar disorder.

Let’s get into some background science and then go into how BDNF and serotonin work together.

Background on BDNF:

You may think that you only have the brain cells that you were born with.  Perhaps your parents told you this when you were a teenager to prevent you from drinking :-)

However, research now shows that you can actually add brain cells in certain areas of your brain, especially in the hippocampus. You can also increase the connections between the neurons, increasing the plasticity of the brain.

BDNF is the key to producing more neurons.

BDNF stands for a brain-derived neurotrophic factor.  It is a type of protein called a neurotrophin.  BDNF works in several ways:

  • BDNF encourages new neuronal growth from stem cells
  • it protects neurons from injury and cell death
  • it improves neuronal function (important in learning and mood)

To improve the way the neurons function, BDNF binds to receptors that are located in the synapses between neurons. BDNF potentiates, or increases, the signal from one neuron to the next.

In addition to being found in the brain, BDNF is also found in the peripheral nervous system – helping muscle nerves to function well.  This connection with muscles is one way that exercise increases BDNF.

Studies on BDNF show:

  • Chronic stress causes a decrease in BDNF. [ref]
  • Low BDNF is linked to Alzheimer’s disease[ref] and Parkinson’s[ref][ref]
  • People with depression usually have lower levels of BDNF.[ref][ref][ref]
  • Mothers with postpartum or during pregnancy depression have low BDNF[ref] and elderly people with depression also have low BDNF. [ref]
  • Low BDNF is linked to obesity.[ref]

BDNF doesn’t necessarily act alone in causing diseases. It often interacts with neurotransmitters or cytokines. For example, a recent study found that in people with schizophrenia, lower BDNF levels correlated with higher IL-2 (interleukin-2) levels.  IL-2 is an inflammatory cytokine that is part of the immune system.[ref]

BDNF Genetic Variant:

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There is one well studied genetic variant in the BDNF gene. (Literally, thousands of studies on it…) It is knowns as the Val66Met (rs6265) variant.

Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):

  • T/T:  decreased BDNF[ref] referred to in studies as Met/Met
  • C/T: somewhat decreased BDNF, referred to as Val/Met
  • C/C: typical BDNF, referred to as Val/Val

Members: Your genotype for rs6265 is .

The T allele (decreased BDNF in the brain) is linked in studies to:

  • decreased hippocampus volume if exposed to early life stress[ref]
  • altered learning and recall [ref][ref]
  • more likely to be overweight[ref]
  • increased anxiety and altered response to antidepressants [ref]
  • less likely to respond to citalopram and escitalopram (Celexa and Lexapro, antidepressants).[ref] Note that this doesn’t mean that those antidepressants absolutely won’t work, just that a larger proportion of people carrying the T allele didn’t respond compared with people carrying the C/C genotype

Not all studies show that the rs6265 T allele affects depression or anxiety.[ref]  There are a lot of conflicting studies that muddy the water…  It isn’t as simple as T-allele = bad brain. 

First, there are lifestyle factors that increase or decrease BDNF (more on these in the Lifehacks section below).

Second, other genetic variants are important. Such as the serotonin gene variant below.

Third, the T-allele is also linked with positive traits such as being more resistant to social defeat. [ref]  The song lyrics “I get knocked down, but I get up again, You are never gonna keep me down…” may apply to people with the T-allele.

Background on Serotonin:

Serotonin is often thought of as a happy neurotransmitter and is linked to feelings of wellbeing. (Serotonin does a lot of things in the body and is not just in the brain. But here I’m just focusing on its role as a brain neurotransmitter.)

Tons of research has been done showing that there is a link between serotonin and depression.  To sum up the research: depression and serotonin are probably linked, somehow. Yep, pretty wishy-washy for decades of research. Again, it doesn’t seem like there are simple answers here such as simply increasing serotonin to cure depression.

Serotonin works as a neurotransmitter to transmit signals in a variety of neurons in the brain. It is released by a neuron into the synapses and then binds to the next neuron causing the signal to be transmitted.

Whole books could be (and have been) written on serotonin and depression.  Instead of getting too deep into the weeds here, I’m going to dive into one specific serotonin receptor…

HTR1A Serotonin Receptor:

The serotonin receptor known as 5-HT1A is coded for by the HTR1A gene. Here, I’m just going to call it the serotonin 1A receptor.  (There are a bunch of different serotonin receptors that do different things in the body.)

Basically, serotonin gets released by one neuron into the space (synapse) next to the beginning of the next neuron. Then serotonin binds to receptors on the next neuron, triggering a reaction that sends the signal along. The receptors are specific to serotonin — in this case, we’re talking about the serotonin 1A receptor.

BDNF is also active in the brain and potentiates the release of serotonin.[ref] It gives it a boost. Like adding nitrous to your car. OK, maybe not that big of a boost.

Research shows the serotonin 1A receptor variant is linked to depression. A new study now points to an interaction between the serotonin receptor variant and the BDNF variant when it comes to depression.

Check your genetic data for rs6295 (23andMe v4, v5):

  • C/C: typical risk of depression*
  • C/G: linked with an increased risk of depression
  • G/G: linked with an increased risk of depression in most (but not all) studies [ref]

Members: Your genotype for rs6295 is .

* Given in plus orientation to match 23andMe data

A meta-analysis looked at several different studies on rs6295 found that it was linked with an increased risk of depression in Asian populations.[ref] Not all studies agree, of course. [ref]

How these BDNF and serotonin variants combine:

While each of these variants has been linked to an increase in mood disorders on their own, not all studies agree and the increase in risk isn’t all that large. Kind of like something is missing from the picture when you look at each gene separately.

The key to the increased risk of depression and anxiety disorders due to the serotonin 1a receptor and BDNF variants may be the combination of the risk alleles.

A recent study looked at the combined effects of carrying both the serotonin 1a receptor (rs6295) variant and the BDNF rs6265 variant.[ref]

The study used PET scan imaging of the brains of people with affective disorders (depression, bipolar, anxiety disorders) and at least three copies of the variant alleles (combos of rs6295 G-alleles and rs6265 T-alleles).  The brain imaging showed that the risk variants altered the serotonin 1a receptor binding in ways associated with affective disorders.


There are several different ways that you can increase BDNF levels:

Exercise has been shown in multiple studies to reliably increase BDNF levels.  It is thought that this is one way that exercise decreases depression for some people. [ref]  Specifically, aerobic activity or endurance-type exercises are best for increasing BDNF. [ref]

Lion’s Mane mushroom extract has been shown to increase BDNF levels. This makes sense in context with all of the studies showing the neuroprotective effects of Lion’s Mane. [ref]  Lion’s mane is available as a supplement online and also combined with coffee (one of my personal favorites:-). You also may be able to find fresh Lion’s mane mushrooms at your local farmer’s market. They are quite tasty!

Anthocyanin, a flavonoid found in blueberries, has been shown in animal studies to increase BDNF in the brain. The levels used were similar to adding more blueberries into the diet or taking a blueberry supplement. [ref]  Yes, there are blueberry supplements available online, but blueberries are delicious and easy to add to your diet… especially when in season!

Milk thistle increases BDNF in depressed rats. [ref]

Related Genes and Topics:

Bipolar disorder and the circadian clock genes:
New research shows that depression and bipolar disorder are linked to changes or disruption in circadian genes. Some people carry genetic variants in the circadian genes that make them more susceptible to circadian disruption.

Tryptophan is an amino acid that the body uses to make serotonin and melatonin. Genetic variants can impact the amount of tryptophan that is used for serotonin. This can influence mood, sleep, neurotransmitters, and immune response.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.