Eccentric medium spiny neuron (eMSN)

On the topic of links to the striatum, next to eMSN, HTT, and GPR52, there's also TSHZ3, which was a significant hit in Paolo's meta-analysis (not DecodeME alone).

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A bit more speculative perhaps, but knockout experiments of these genes in mice found changes in corticostriatal glutamatergic transmission. This was in the context of autism research.
These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, ∼50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits.
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Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior - PubMed
 
ME/CFS Science Blog said:
Zooming in on the Saunders et al. 2018 paper that discovered eMSN.
Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain - PubMed
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The next major data source is the brain atlas by Siletti et al. 2023.
Transcriptomic diversity of cell types across the adult human brain - PubMed

They did the same single-cell RNA sequencing of the brain but in 3 human donors. They found 461 clusters for cell types, but there were also 31 superclusters that form larger groups. Interestingly, eMSN were one of these superclusters, which indicates that their genetic profile really sets them apart; they aren't just a minor modification of MSN.

Here's a nice overview of the results:
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This graph shows where the eMSN (my highlighting in yellow) are mostly found. Mostly in the cerebral nuclei but also a bit in the cortex, thalamus, and hypothalamus.
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These two papers, the mouse atlas by Saunders et al. 2018 (sometimes called DropViz) and the human brain atlas by Siletti et al. are the two main data sources that Paolo also used in his analysis. He took the DNA results of ME/CFS patients and checked how these compared to the cell types specified in these two studies.
 
A clarification that I didn't notice before: the human atlas mentions that most eMSN only have DRD1. Those with both DRD1 and DRD2 were a regional specialization in the basal ganglia.
Two superclusters corresponded to the cerebral nuclei’s dopamine receptor–expressing medium spiny neurons (MSNs) and CASZ1+ eccentric MSNs(Fig. 2A; fig. S2, A to F; and Materials and methods) (5). Most eccentric MSNs expressed only DRD1, but many in the basal ganglia coexpressed DRD1 and DRD2, suggesting regional specialization
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EDIT: here's figure 2 form the supplementary material:

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Robert 1973 said:
Would it be worth contacting Saunders [no relation] or any of the other authors about the possible connection to ME/CFS?
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Possibly, but their paper mapped out the entire brain, and their data is relevant for 100s of medical conditions. It wasn't focused on eMSN in particular; they just happened to find it when mapping the entire brain.

But with eMSN being largely unknown and there being a connection to ME/CFS, I think this opens up a lot of research options, including animal models where they can better study how these cells behave (i.e. do they play a role in sickness behavior?). Suspect there are lots of research groups that can do this type of work. We also need brain studies focused on the striatal region.

Once we have written out our thoughts on this, it might be worth doing outreach emails to teams with the right expertise. For the first time in 40 years, ME/CFS research might have a solid lead.
 
I see dopamine mentioned quite a bit in the eMSN discussions. Could the way Abilify works affect the functioning of eMSN? I thought it interesting with anecdotal stories from people where Abilify helped how many of them found that they each had their own sweet spot for Abilify dose level - not too much, not too little - especially interesting if eMSN do have both D1 and D2 receptors?

I had no luck asking the internet. S4ME is now quoted in many answers.
 
One caveat is that the eMSN data is relatively new, discovered in 2018 and included in the human brain atlas in 2023.

So a lot of GWAS from other diseases might not have tested for this cell type yet. Perhaps if they did, it would be connected to a lot of brain diseases and behavioral traits and turn out to be not very specific to ME/CFS.
 
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