Is there a firm consensus in the MRS community on what changes in brain myoinositol are most likely to reflect functionally (glial processes vs osmotic/volume regulation)?
It seems to me like myo-inositol is well established as a brain osmolyte but I see many MRS papers interpret myo-inositol as a glial marker. I do understand that myo-inositol is supposedly more abundant in glial cells than in neurons (Brand et al 1993) but I’m confused as to why the glial-marker interpretation seems to be the default interpretation for myoinositol differences given its other functional roles and the biological ambiguity about which of its roles could be responsible for differences.
thank you!
steph
Thurston et al., 1989, “Myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain” (chronic hypo-/hypernatremia). DOI: 10.1203/00006450-198910000-00010
Videen et al., 1995, Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study.
I guess this probably comes from the diffusion MRS world. For instance in the recent consensus paper it is written:
Although the exact distributions of metabolites across cell types in unknown, it is generally accepted that myo-inositol (Ins) and choline compounds (tCho = glycerophosphocholine, GPC + phopsphorylcholine, PCho) are preferentially found inside astrocytes and glutamate (Glu) and NAA in neurons[5]-[7].
Though how much work preferentially is doing in that sentence, I don’t have a good idea. @Clemence, can you give any more of an idea of how preferentially mIns is compartmentalised into glia from the dMRS point of view?
That’s a good question !
The way we think of metabolic compartmentation has been built with the following steps:
in the 2000s, in vitro cell culture studies indicate that myo inositol is more concentrated in astrocytes than in neurons
See: Griffin et al., NMR in Biomed, 2002, DOI:10.1002/nbm.792 (e.g. Fig 2)
See: Fisher et al., Journal of Neuroschemistry, 2002, [https://doi.org/10.1046/j.1471-4159.2002.01041.x] (Table 1: myo inositol concentration in rat cerebral cortex astrocytes is reported to be 12-15mM, whilst it is 2-4mM in the rat cerebral cortex with all cell types: it indicates that myopic inositol is therefore at least 3 times more concentrated in astrocytes than in neurons).
in the 2010s, some animal and human studies reporting higher myo-inositol concentration with neuroinflammation
in the study of Palombo et al., PNAS, 2016 (https://doi.org/10.1073/pnas.1504327113) we showed that myo-inositol and choline compounds diffuse in glial-like structures (with a completely agnostic model), compared to tNAA and glutamate for instance which diffuse in larger and more complex structures (neuron-like). This is an other sign indicating that myo-inositol is more concentrated in glia.
in a model of induced astrocytic activation (Ligneul et al., NeuroImage, 2019), we showed that myo-inositol diffusion properties reflected well the astrocytic reactivity.
Of course, if there is a metabolic alteration (involving particularly the inositol production path), this preferential compartmentation can be questionned! I suppose it is the default interpretation in dMRS studies, as @wclarke says, because in theory, if the metabolic repartition remains similar (i.e. if the change in mIns concentration affects all compartments in a similar way), the diffusion properties should still reflect the compartment where it is more concentrated. Of course now, if there is a pathology where myo-inositol concentration is preferentially decreased in astrocytes or preferentially increased in neurons, it will affect the interpretation (but again, myo-inositol diffusion properties would give us an indication of the size/shape of the compartment where it is located).
One interesting paper states that “there is also little correlation between inositol concentrations and levels of glial-fibrillary acidic protein, a glial cell marker [359]”.
I find another paper pretty intriguing though, too. It found correlations between mIns and [11C]-PBR28, a tracer that marks the 18 kDa translocator protein (TSPO), which gets increasingly expressed in microglia and astrocytes upon activation, e.g., in neuroinflammation.
At the end of the day, it’ll depend very strong on the context. The osmolyte interpretation holds pretty strong in some cases, for example, in hepatic encephalopathy, where the cells release mIns to counter the massive Gln accumulation.