<p>You may have heard the adage <a href="https://en.wikipedia.org/wiki/The_dose_makes_the_poison" rel="nofollow noreferrer">the dose makes the poison</a>. Excitotoxicity is generally not a <em>good</em> thing or something that cells are built to do intentionally, it's a consequence of a malfunction. It's a bit like asking the question &quot;why is speed both responsible for getting a car where it's going and also for leading to damage when a car strikes another object?&quot; The whole reason the car is at threat for the latter is that the former is necessary for its purpose; if cars didn't need to move to be useful, they'd have lower risk of crashing. If neurons didn't need to communicate and change to be useful, they wouldn't experience excitotoxicity.</p>
<p>Calcium is the key player here: calcium is an important signaling molecule in cells. Time and intensity are both important for calcium: you can read on the <a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" rel="nofollow noreferrer">synaptic plasticity</a> Wikipedia page how calcium is involved in both long-term potentiation (strengthening synapses) and long-term depression (weakening synapses). In both cases it's driven by a calcium <em>increase</em>. The rough signaling logic is no calcium change = no synaptic change, small but long-lasting calcium change = synaptic depression, large and brief calcium change = synaptic potentiation.</p>
<p>Calcium is involved in lots of other processes in cells, too, and through ordinary neurotransmission these processes either aren't activated (perhaps because they're far from the synapses) or are affected weakly; with excitotoxicity, calcium is a bit out of control.</p>
<p>Excitotoxicity occurs in extreme circumstances, like seizures (where the balance between excitation and inhibition is off in some way) or stroke (where there isn't energy available to keep up with ion concentration gradients. There is no healthy situation that would lead to excitotoxicity, there must be some pathology.</p>

CC BY-SA 4.0
2023-04-07T22:54:34.253Z
I should have worded my question a bit better, I primarily wanted to know whether LTP alone could lead to excitotoxicity under normal conditions between two functioning cells. Thanks for the edit, your last paragraph answers my question. If you don't mind though, would you be able to clarify whether my assumption over neurotransmitter quanta increase due to LTP is correct?
Pickle Rick
CC BY-SA 4.0
2023-04-07T22:57:03.710Z
@PickleRick The Wikipedia article you linked talked about LTP mechanisms. LTP occurs through modulation of post-synaptic *receptors*, not neurotransmitter release. The latter can also be controlled through other mechanisms, but not the thing usually called "LTP". I'm not certain what all the constraints are on post-synaptic receptor density; there's going to be some physical limit, since receptors take up space in the membrane. Some portion of plasticity is based in receptor trafficking: whether receptors are located in the membrane or in endosomes.
Bryan Krause
CC BY-SA 4.0
2023-04-07T22:59:05.457Z
...once you've moved all the available receptors to the membrane, there's no more to move. There are longer-term LTP effects that involve synthesis of more receptors, but that's going to be somehow limited, too, though I'm not sure what the precise limiting factors are. Neurons overall attempt to maintain some level of homeostasis by multiple mechanisms, too, so that neurons that are being excited a lot *generally* will undergo other changes to *be less excited*: that might include scaling all synapses down, increasing responsiveness to inhibition, or changing membrane properties.
Bryan Krause
CC BY-SA 4.0
2023-04-07T23:01:51.143Z
I think people outside of neuroscience also don't realize the scale. A single neuron gets thousands to tens of thousands of inputs, not just a handful. Any one input is pretty minor in the scheme of things. It's simultaneous activation of multiple synapses that makes a cell fire. The conditions leading to excitotoxicity are things that are affecting all the synapses at once, the whole brain or at least whole regions.
Bryan Krause
CC BY-SA 4.0
2023-04-07T23:07:38.373Z
Thanks so much for the fast and detailed response. I may not be a neuroscientist, but I've read many technical books (Dendrites, Neuroscience Purves, etc.) and hope to learn far more, it's endlessly fascinating. As for a single input being pretty minor in the scheme of things, I'm aware, my favorite neuron happens to be the Purkinje Cell. Simply beautiful. I also just recently, earlier today, was looking at the following dataset provided by Google in Neuroglancer. https://h01-dot-neuroglancer-demo.appspot.com/#!gs://h01-release/assets/neuroglancer_states/20210601/gallery/z_4k_axons.json
Pickle Rick
CC BY-SA 4.0
2023-04-07T23:10:41.277Z
Of course, passion and self learning doesn't equate to a neuroscience degree, but I'm sure I will have many more questions in the future on this board to further my knowledge from the experts like yourself. Thanks again. :)
Pickle Rick
CC BY-SA 4.0
2023-04-07T23:16:45.960Z
Indeed, feel free to ask here - questions tend to be best received when they're supported by something, so ideally motivated by things you're reading, like this one was, rather than just things off the top of your head (where it's better to try to read a bit first before asking).
Bryan Krause
CC BY-SA 4.0
2023-04-07T22:37:41.497Z
2023-04-07T22:48:11.697Z
2023-04-07T22:48:11.697Z
Bryan Krause
<p>Here are two quotes from Wikipedia with their respective pages.</p>
<p><a href="https://en.wikipedia.org/wiki/Synaptic_plasticity" rel="nofollow noreferrer">Synaptic Plasticity</a>
&quot;Two molecular mechanisms for synaptic plasticity involve the NMDA and AMPA glutamate receptors. <strong>Opening of NMDA channels (which relates to the level of cellular depolarization) leads to a rise in post-synaptic Ca2+ concentration and this has been linked to long-term potentiation, LTP</strong> (as well as to protein kinase activation); strong depolarization of the post-synaptic cell completely displaces the magnesium ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg2+ ions, resulting in less Ca2+ entering the post-synaptic neuron and lower intracellular Ca2+ concentrations (which activate protein phosphatases and induce long-term depression, LTD).&quot;</p>
<p><a href="https://en.wikipedia.org/wiki/Excitotoxicity" rel="nofollow noreferrer">Excitotoxicity</a>
&quot;For example, when glutamate receptors such as the <strong>NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell.</strong> Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.&quot;</p>
<p>This implies that the same process responsible for strengthening synapses can also lead to cell death, but it's unclear to me what mechanism mitigates this or even whether they're directly related. Is the quanta of neurotransmitter in the presynaptic vesicles increased at an exponentially smaller rate as it strengthens, making it exceedingly unlikely that it would lead to excitotoxicity? If so, is excitotoxicity at such sites triggered due to some unrelated malfunction, such as a nearby cell &quot;leaking&quot; neurotransmitter into the extracellular space? Are normally functioning cells capable of undergoing excitotoxicity solely due to synaptic strengthening via LTP?</p>

<neuroscience><plasticity>
Why is the same process responsible for both synaptic strengthening and excitotoxicity?
Pickle Rick
# Why is the same process responsible for both synaptic strengthening and excitotoxicity?

(Asked by: username_0 on 2023-04-07)

Here are two quotes from Wikipedia with their respective pages.

[Synaptic Plasticity](https://en.wikipedia.org/wiki/Synaptic_plasticity)
"Two molecular mechanisms for synaptic plasticity involve the NMDA and AMPA glutamate receptors. **Opening of NMDA channels (which relates to the level of cellular depolarization) leads to a rise in post-synaptic Ca2+ concentration and this has been linked to long-term potentiation, LTP** (as well as to protein kinase activation); strong depolarization of the post-synaptic cell completely displaces the magnesium ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg2+ ions, resulting in less Ca2+ entering the post-synaptic neuron and lower intracellular Ca2+ concentrations (which activate protein phosphatases and induce long-term depression, LTD)."

[Excitotoxicity](https://en.wikipedia.org/wiki/Excitotoxicity)
"For example, when glutamate receptors such as the **NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell.** Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA."

This implies that the same process responsible for strengthening synapses can also lead to cell death, but it's unclear to me what mechanism mitigates this or even whether they're directly related. Is the quanta of neurotransmitter in the presynaptic vesicles increased at an exponentially smaller rate as it strengthens, making it exceedingly unlikely that it would lead to excitotoxicity? If so, is excitotoxicity at such sites triggered due to some unrelated malfunction, such as a nearby cell "leaking" neurotransmitter into the extracellular space? Are normally functioning cells capable of undergoing excitotoxicity solely due to synaptic strengthening via LTP?

**Tags:** neuroscience, plasticity


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## 1 answers

### Answer by username_1 on 2023-04-07. Score: 2 | Accepted answer

You may have heard the adage [the dose makes the poison](https://en.wikipedia.org/wiki/The_dose_makes_the_poison). Excitotoxicity is generally not a *good* thing or something that cells are built to do intentionally, it's a consequence of a malfunction. It's a bit like asking the question "why is speed both responsible for getting a car where it's going and also for leading to damage when a car strikes another object?" The whole reason the car is at threat for the latter is that the former is necessary for its purpose; if cars didn't need to move to be useful, they'd have lower risk of crashing. If neurons didn't need to communicate and change to be useful, they wouldn't experience excitotoxicity.

Calcium is the key player here: calcium is an important signaling molecule in cells. Time and intensity are both important for calcium: you can read on the [synaptic plasticity](https://en.wikipedia.org/wiki/Synaptic_plasticity) Wikipedia page how calcium is involved in both long-term potentiation (strengthening synapses) and long-term depression (weakening synapses). In both cases it's driven by a calcium *increase*. The rough signaling logic is no calcium change = no synaptic change, small but long-lasting calcium change = synaptic depression, large and brief calcium change = synaptic potentiation.

Calcium is involved in lots of other processes in cells, too, and through ordinary neurotransmission these processes either aren't activated (perhaps because they're far from the synapses) or are affected weakly; with excitotoxicity, calcium is a bit out of control.

Excitotoxicity occurs in extreme circumstances, like seizures (where the balance between excitation and inhibition is off in some way) or stroke (where there isn't energy available to keep up with ion concentration gradients. There is no healthy situation that would lead to excitotoxicity, there must be some pathology.

> **Comments:**
> **username_0**: I should have worded my question a bit better, I primarily wanted to know whether LTP alone could lead to excitotoxicity under normal conditions between two functioning cells. Thanks for the edit, your last paragraph answers my question. If you don't mind though, would you be able to clarify whether my assumption over neurotransmitter quanta increase due to LTP is correct?  
> **username_1**: @PickleRick The Wikipedia article you linked talked about LTP mechanisms. LTP occurs through modulation of post-synaptic *receptors*, not neurotransmitter release. The latter can also be controlled through other mechanisms, but not the thing usually called "LTP". I'm not certain what all the constraints are on post-synaptic receptor density; there's going to be some physical limit, since receptors take up space in the membrane. Some portion of plasticity is based in receptor trafficking: whether receptors are located in the membrane or in endosomes.  
> **username_1**: ...once you've moved all the available receptors to the membrane, there's no more to move. There are longer-term LTP effects that involve synthesis of more receptors, but that's going to be somehow limited, too, though I'm not sure what the precise limiting factors are. Neurons overall attempt to maintain some level of homeostasis by multiple mechanisms, too, so that neurons that are being excited a lot *generally* will undergo other changes to *be less excited*: that might include scaling all synapses down, increasing responsiveness to inhibition, or changing membrane properties.  
> **username_1**: I think people outside of neuroscience also don't realize the scale. A single neuron gets thousands to tens of thousands of inputs, not just a handful. Any one input is pretty minor in the scheme of things. It's simultaneous activation of multiple synapses that makes a cell fire. The conditions leading to excitotoxicity are things that are affecting all the synapses at once, the whole brain or at least whole regions.  
> **username_0**: Thanks so much for the fast and detailed response. I may not be a neuroscientist, but I've read many technical books (Dendrites, Neuroscience Purves, etc.) and hope to learn far more, it's endlessly fascinating. As for a single input being pretty minor in the scheme of things, I'm aware, my favorite neuron happens to be the Purkinje Cell. Simply beautiful. I also just recently, earlier today, was looking at the following dataset provided by Google in Neuroglancer. https://h01-dot-neuroglancer-demo.appspot.com/#!gs://h01-release/assets/neuroglancer_states/20210601/gallery/z_4k_axons.json  
> **username_0**: Of course, passion and self learning doesn't equate to a neuroscience degree, but I'm sure I will have many more questions in the future on this board to further my knowledge from the experts like yourself. Thanks again. :)  
> **username_1**: Indeed, feel free to ask here - questions tend to be best received when they're supported by something, so ideally motivated by things you're reading, like this one was, rather than just things off the top of your head (where it's better to try to read a bit first before asking).  

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