<p>This is a fairly open-ended question...  One example of the potentially negative consequences of overexpressed BDNF is its effect on the likelihood and frequency of epileptic seizures.</p>
<p>I guess the short version of this effect is that BDNF appears to <a href="https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor#Synaptogenesis" rel="nofollow noreferrer">promote neuronal growth</a>, including neurogenesis, axonal and synaptic sprouting, and neuronal excitation, in exactly the areas of the brain that are associated with epilepsy.  <a href="https://en.wikipedia.org/wiki/Epileptic_seizure#Mechanism" rel="nofollow noreferrer">Epileptic seizures</a> are essentially hyper-excitations of neurons, so any factor that increases the excitability of neurons in brain areas associated with seizures can be a culprit.</p>
<p>A good, fairly recent, and open access review of the role of BDNF and its primary receptor TrkB in epilepsy is <a href="https://pubmed.ncbi.nlm.nih.gov/22787630/" rel="nofollow noreferrer">McNamara &amp; Scharfman (2012)</a>:</p>
<blockquote>
<p>Intrahippocampal infusion of BDNF and transgenic overexpression of
BDNF or TrkB increase seizure susceptibility or severity. Conditional
knockout of TrkB eliminated epileptogenesis altogether in the kindling
model.</p>
</blockquote>
<p>That is, in epileptic mice, adding BDNF increased seizure frequency, and removing it eliminated seizures entirely.  The authors suggest several mechanisms by which this might happen:</p>
<blockquote>
<p>... long-term potentiation (LTP) of excitatory synapses between
principal cells may contribute to limbic epileptogenesis; that
is, potentiation of these synapses may facilitate propagation of
seizure activity through synaptically-coupled neuronal populations
throughout the limbic system and beyond.</p>
<p>One interesting possibility is that enhanced TrkB activation reduces
expression of the K-Cl cotransporter, KCC2, ... an important molecular
and cellular mechanism contributing to limbic epilepsy.</p>
<p>The effect of estrogen on NPY levels could be mediated by BDNF,
because BDNF induces NPY synthesis following TrkB activation</p>
</blockquote>
<p>In other words, (1) BDNF-induced <a href="https://en.wikipedia.org/wiki/Long-term_potentiation" rel="nofollow noreferrer">LTP</a> - the mechanism that underlies memory and learning - increases the excitability of neurons, potentially causing seizures; (2) BDNF may inhibit <a href="https://en.wikipedia.org/wiki/Chloride_potassium_symporter_5" rel="nofollow noreferrer">KCC2</a>, itself a synpatic inhibitor, again increasing the excitability of neurons; and (3) hormone-induced BDNF may moderate neuron hyper-excitability through its effect on yet another protein, the neurotransmitter <a href="https://en.wikipedia.org/wiki/Neuropeptide_Y" rel="nofollow noreferrer">NPY</a>.</p>
<p>Another recent review, though not open access, is <a href="https://doi.org/10.1016/j.npep.2018.09.005" rel="nofollow noreferrer">Iughetti et al (2018)</a>.  Similar to the previous review:</p>
<blockquote>
<p>... BDNF has excitatory effects in neuronal cultures and animal brain
slices.  Furthermore, both BDNF and its conjugated receptor (... TrkB)
are increased  in animal models and humans with epilepsy, particularly
in the temporal and hippocampal areas. Acute injection of BDNF in
brain of mice induces seizures, which are almost or totally abolished
[by] blocking its transcription and pathway.</p>
</blockquote>
<p>The authors also implicate the effects of BDNF on axonal sprouting and neuronal hyper-excitability, KCC2 and NKCC1 downregulation, and NPY synthesis on seizure likelihood and frequency.</p>
<p>Neurochemistry is complex and not well understood, and there is indication that BDNF can also have protective properties against epilepsy under certain conditions (eg, long-term in low doses).  Lots more detail is available in the reviews cited.</p>

CC BY-SA 4.0
2019-06-23T16:48:19.743Z
But if ketones trigger the production of BDNF, then why do keto diets help epilepsy?
Alundaio
CC BY-SA 4.0
2019-06-23T17:18:57.873Z
@Alundaio As far as I know, the suspected anti-seizure effects of ketones are not proposed to mediate via BDNF - ie, they are neuroprotective via some other mechanism that presumably bypasses any harmful effects.
Arnon Weinberg
CC BY-SA 4.0
2019-05-05T07:05:43.487Z
2022-11-23T07:24:28.253Z
2022-11-23T07:24:28.253Z
Arnon Weinberg
<p>Because the too high expression will cause to lose specificity in the process of neural plasticity because it would make synapses too easy to make. Synapses that didn't should be made.
The trkb receptor will exist in lower ammounts too, it is a protective mechanism, I think.
The last thing that I can think it is the too easy LTP, that is stimulated by BDNF itself by interaction of TRKB with NA+ pumps</p>

CC BY-SA 4.0
2018-10-25T20:02:56.347Z
2018-10-25T20:02:56.347Z
Victor Fonseca
<p>I am interested in looking at the effects of too much <a href="https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor" rel="nofollow noreferrer">BDNF</a> and other proteins such as <a href="https://en.wikipedia.org/wiki/RE1-silencing_transcription_factor" rel="nofollow noreferrer">repressor element one silencing transcription factor (REST)</a>. Most research suggest that elevated levels are protective, however there is a small amount of research suggesting that too much (over expression) may actually be detrimental (<a href="http://www.sciencedirect.com/science/article/pii/S0969996108002775" rel="nofollow noreferrer">Cunha, et al. 2009</a>).</p>

<blockquote>
  <p>Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.</p>
</blockquote>

<p>I was wondering if there is any more research, or theories as to why too much of a protein that is considered to be protective could be harmful? Thank you.</p>

<h2>References</h2>

<p>Cunha, C., et al. (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. <em>Neurobiology of Disease</em>, 33(3), pp. 358—368<br>DOI: <a href="https://doi.org/10.1016/j.nbd.2008.11.004" rel="nofollow noreferrer">10.1016/j.nbd.2008.11.004</a></p>

CC BY-SA 4.0
2019-04-29T18:11:09.137Z
Here are two more papers on BDNF-overexpressing transgenic mice:

Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age https://doi.org/10.1016/j.bbr.2014.04.025

Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice https://doi.org/10.1101/lm.2213711
Angela Pretorius
<neuroscience><cognitive-neuroscience><memory><depression>
Why could too much BDNF be detrimental in terms of depression and memory?
user16083
# Why could too much BDNF be detrimental in terms of depression and memory?

(Asked by: username_0 on 2017-06-16)

I am interested in looking at the effects of too much [BDNF](https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor) and other proteins such as [repressor element one silencing transcription factor (REST)](https://en.wikipedia.org/wiki/RE1-silencing_transcription_factor). Most research suggest that elevated levels are protective, however there is a small amount of research suggesting that too much (over expression) may actually be detrimental ([Cunha, et al. 2009](http://www.sciencedirect.com/science/article/pii/S0969996108002775)).

> Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

I was wondering if there is any more research, or theories as to why too much of a protein that is considered to be protective could be harmful? Thank you.

## References

Cunha, C., et al. (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. *Neurobiology of Disease*, 33(3), pp. 358—368  
DOI: [10.1016/j.nbd.2008.11.004](https://doi.org/10.1016/j.nbd.2008.11.004)

**Tags:** neuroscience, cognitive-neuroscience, memory, depression

> **Comments:**
> **username_1**: Here are two more papers on BDNF-overexpressing transgenic mice:  Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age https://doi.org/10.1016/j.bbr.2014.04.025  Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice https://doi.org/10.1101/lm.2213711  

---

## 2 answers

### Answer by username_2 on 2019-05-05. Score: 3

This is a fairly open-ended question... One example of the potentially negative consequences of overexpressed BDNF is its effect on the likelihood and frequency of epileptic seizures.

I guess the short version of this effect is that BDNF appears to [promote neuronal growth](https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor#Synaptogenesis), including neurogenesis, axonal and synaptic sprouting, and neuronal excitation, in exactly the areas of the brain that are associated with epilepsy. [Epileptic seizures](https://en.wikipedia.org/wiki/Epileptic_seizure#Mechanism) are essentially hyper-excitations of neurons, so any factor that increases the excitability of neurons in brain areas associated with seizures can be a culprit.

A good, fairly recent, and open access review of the role of BDNF and its primary receptor TrkB in epilepsy is [McNamara & Scharfman (2012)](https://pubmed.ncbi.nlm.nih.gov/22787630/):

> Intrahippocampal infusion of BDNF and transgenic overexpression of
> BDNF or TrkB increase seizure susceptibility or severity. Conditional
> knockout of TrkB eliminated epileptogenesis altogether in the kindling
> model.

That is, in epileptic mice, adding BDNF increased seizure frequency, and removing it eliminated seizures entirely. The authors suggest several mechanisms by which this might happen:

> ... long-term potentiation (LTP) of excitatory synapses between
> principal cells may contribute to limbic epileptogenesis; that
> is, potentiation of these synapses may facilitate propagation of
> seizure activity through synaptically-coupled neuronal populations
> throughout the limbic system and beyond.
>
> One interesting possibility is that enhanced TrkB activation reduces
> expression of the K-Cl cotransporter, KCC2, ... an important molecular
> and cellular mechanism contributing to limbic epilepsy.
>
> The effect of estrogen on NPY levels could be mediated by BDNF,
> because BDNF induces NPY synthesis following TrkB activation

In other words, (1) BDNF-induced [LTP](https://en.wikipedia.org/wiki/Long-term_potentiation) - the mechanism that underlies memory and learning - increases the excitability of neurons, potentially causing seizures; (2) BDNF may inhibit [KCC2](https://en.wikipedia.org/wiki/Chloride_potassium_symporter_5), itself a synpatic inhibitor, again increasing the excitability of neurons; and (3) hormone-induced BDNF may moderate neuron hyper-excitability through its effect on yet another protein, the neurotransmitter [NPY](https://en.wikipedia.org/wiki/Neuropeptide_Y).

Another recent review, though not open access, is [Iughetti et al (2018)](https://doi.org/10.1016/j.npep.2018.09.005). Similar to the previous review:

> ... BDNF has excitatory effects in neuronal cultures and animal brain
> slices. Furthermore, both BDNF and its conjugated receptor (... TrkB)
> are increased in animal models and humans with epilepsy, particularly
> in the temporal and hippocampal areas. Acute injection of BDNF in
> brain of mice induces seizures, which are almost or totally abolished
> [by] blocking its transcription and pathway.

The authors also implicate the effects of BDNF on axonal sprouting and neuronal hyper-excitability, KCC2 and NKCC1 downregulation, and NPY synthesis on seizure likelihood and frequency.

Neurochemistry is complex and not well understood, and there is indication that BDNF can also have protective properties against epilepsy under certain conditions (eg, long-term in low doses). Lots more detail is available in the reviews cited.

> **Comments:**
> **username_3**: But if ketones trigger the production of BDNF, then why do keto diets help epilepsy?  
> **username_2**: @username_3 As far as I know, the suspected anti-seizure effects of ketones are not proposed to mediate via BDNF - ie, they are neuroprotective via some other mechanism that presumably bypasses any harmful effects.  

---

### Answer by username_4 on 2018-10-25. Score: -1

Because the too high expression will cause to lose specificity in the process of neural plasticity because it would make synapses too easy to make. Synapses that didn't should be made.
The trkb receptor will exist in lower ammounts too, it is a protective mechanism, I think.
The last thing that I can think it is the too easy LTP, that is stimulated by BDNF itself by interaction of TRKB with NA+ pumps


---

