Can excitotoxicity kill only certain neurons?

[Vieno]

Is it possible that the process of excitotoxicity would only kill certain neurons leaving others unaffected? I can understand that if the glutamatergic storm only takes place in one place then only that place is affected, but I'm not talking about brain loci now, I'm talking about specific neurons. For example, it is claimed that excitotoxicity plays a role in Parkinson's, so it seems to me like yes, excitotoxicity can only affect certain neurons (as only dopaminergic neurons are killed). But how does this work then? I mean, how can the excess glutamate/whatever excitotoxin that is causing the excitotoxicity discriminate between different neurons? I have no particular interest in Parkinson's, but I feel it's a great example.

Trying to understand how excitotoxicity might contribute to a certain pathology, that's why I'm asking. Suppose that one does not respond at all to agonists of certain receptors. The question is, could the neurons of these receptors be actually dead, and could this have been caused by excitotoxicity.

 

[black53]

Yes, for example MPTP (well actually it's metabolite MPP+) kills mostly just the dopaminergic neurons in the substantia nigra and causes the same symptoms as parkinsons disease. It's actually used to recreate the effects of Parkinsons disease in lab animals so they can study potential treatments for it.

 

[sekio]

Suppose that one does not respond at all to agonists of certain receptors. The question is, could the neurons of these receptors be actually dead, and could this have been caused by excitotoxicity.

It's stupendously unlikely that you could have killed off large portions of your brain and the only effects you'd notice is nothing when you took drugs... for instance, destruction from MPTP results in parkinson's disease, not an intolerance to dopaminergics.

More likely explanation is a freak genetic mutation that stops e.g. psychedelics from binding. They do exist, they're just rare.

 

[Vieno]

Yes, for example MPTP (well actually it's metabolite MPP+) kills mostly just the dopaminergic neurons in the substantia nigra and causes the same symptoms as parkinsons disease. It's actually used to recreate the effects of Parkinsons disease in lab animals so they can study potential treatments for it.

Thanks, I had heard about MPTP/MPP+ but never read more about it. But is it excitotoxicity that this substance causes? Wikipedia refers to it simply as a neurotoxin. Can a specifically excitotoxic process kill only specific neurons, and if so, how does it discriminate?

It's stupendously unlikely that you could have killed off large portions of your brain and the only effects you'd notice is nothing when you took drugs... for instance, destruction from MPTP results in parkinson's disease, not an intolerance to dopaminergics.

More likely explanation is a freak genetic mutation that stops e.g. psychedelics from binding. They do exist, they're just rare.

There are very pronounced symptoms and they partially correlate with symptoms of mice lacking the receptors in question (GABA-B). That's why I think it's a valid question if the neurons of the receptors are dead. Also what I'm suggesting is not the death of neurons producing neurotransmitters, but the death of neurons/synapses containing specific receptors. So unlike in Parkinsonism, reaction to agonists would be abolished.

But you got me curious about those mutations. Could you give some key words/links? I'd really like to learn about them. Do these mutations also prevent the receptors' endogenous ligands from binding?

 

[socko]

..., excitotoxicity can only affect certain neurons (as only dopaminergic neurons are killed). But how does this work then? I mean, how can the excess glutamate/whatever excitotoxin that is causing the excitotoxicity discriminate between different neurons? ...

The answer to your question requires some knowledge of complex cellular signalling events and pathways. There's a lot more to it, and it is the subject of ongoing scientific research, but I'll briefly describe what happens with glutamate excitotoxicity. Glutamate acts on several receptor subtypes. One of them, the NMDA receptor, is highly permeable to calcium. The excess calcium is the main thing that causes the damage. Some cells express high levels of NMDA receptors. Other cells that are be right beside them do not. So when there is excess glutamate in that area of the brain, the cells that express NMDA receptors are going to be flooded with calcium and be more susceptable to excitotoxicity than those that do not. It's more complicated than that, but you get the idea.

The way it works is complicated. When overstimulated with excess amounts of glutamate, for instance during a pathological condition such as stroke or head injury, calcium floods into the cell through overstimulated NMDA receptors/channels. That excess calcium influx is what does the damage.

Glutamte induced elevated calcium levels proceed to depolarize the cell and overactivate a number of enzymes, including PKC, CAMKII, NOS, endonucleases, ornithine decarboxylase, etc. These processes, in turn, activate c-fos and c-jun transcription factors, damage the DNA, cell membrane, organelles, cytoskeletal structure, and lead to cell death through necrosis or apoptosis. The following is speculation, but just like certain cells have more NMDA receptors, some of those cells are more resistant to excitotoxicity. This is an area of ongoing research and little is known. It might be that they have different levels of the enzymes listed above or even have mechanisms that counter the effect and offer some level of neuroprotection. For example, neurons that express different NOS (nitric oxide synthase) levels of and different NOS isoforms have more resistance to excitotoxicity.

See http://www.eurosiva.org/Archive/Vienna/abstracts/Speakers/SUREDA.htm for more details.