The Alteration of Microglial Calcium Homeostasis in Central Nervous System Disorders: A Comprehensive Review
, Faria Tasnim 2,3, Md. Aktaruzzaman 1,2, Md. Tarikul Islam 2,4, Rifat Rayhan 2,5, Afrina Brishti 6, Junguk Hur 6, James E. Porter 6 and Md. Obayed Raihan 2,7,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsAs a general comment, this is a detailed compilation of the Literature about Calcium homeostasis in CNS disorders. A thoughtful review would require that the authors further elaborate on the findings of others based upon their own findings and expertise and present their own hypothesis on the topic. Moreover, CNS disorders are manifold: is microglial calcium dyshomeostasis placed upstream (etiologic role?) or downstream from etiologic factors (collateral damage?) in them all? This question is not discussed enough.
Specific points:
1. In the Title, the word "role" is misleading and should be substituted for by "alteration".
2. In the Introduction (p. 1), the origin of microglia is not correctly reported as microglia differentiation occurs inside the forming nervous system. The existence of a perivascular microglia derived from blood monocytes even in the adult age is ignored.
3. In the "Receptor operated calcium channels" the Calcium sensing receptor has been omitted, although it modulates the function of a TRPC6-encoded channel (Chakravarthy et al. Adv. Exp. Biol. Med. 740, 108, 2012).
4. At p. 16, note that iNOS (inducible nitric oxide synthase) is an enzyme and not a factor.
5. Operative molecular mechanisms driven or hindered by "calcium dyshomeostasis" are often not discussed. For example, at p. 7, how "disruptions in calcium homeostasis can activate the NLRP3 inflammasome"? Moreover, NLRP3 is not the unique microglial inflammasome.
6. Tables should also report at each line pertinent references for quick perusing by the reader.
7. A table or synopsis of calcium channels and their known regulatory mechanisms could also be useful.
8. Monomeric Amyloid-beta is neurotrophic and not neurotoxic (p.18).
9. At p. 19 pls note that beta-secretase acts on many more substrates besides APP: because of this feature beta-secretase inhibitors were not found to be clinically useful in Alzheimer's disease.
10. The lettering in Figure 1 is too small. The Calcium-sensing receptor is not shown in the same Figure and the GPCR notation is too generic.
11. Effects of nuclear changes of Ca2+ levels are nowhere reported.
12. There are frequent text repetitions passim.
Comments on the Quality of English LanguageWords like "Aspect" in Tables at p. 13-15, "Factor" in Table at p. 16-17 should be changed.
There are typos (plurals instead of singulars and vice versa, etc.) passim
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis article reviewed the microglial calcium homeostasis in several CNS disorders. It is interesting and well-written. Here are some recommendations as following:
1. The logic of introduction part is a bit confusing and I suggest to refine it.
2. Mechanosensitive Piezo1 channel can also function as a cell surface Ca2+-permeable channel in microglial cells and mediate Ca2+ influx to increase intracellular Ca2+ concentrationï¼›It can be added to the “a Calcium channels, pumps, and exchangers in microglia” section and Figure 1.
3. I recommend that the authors review references carefully. Some references are missing. For example, section “b Parkinson’s diseases and altered calcium signaling in microglia”, the 2nd paragraph, “In animal models of hemi-parkinsonism created by 6-OHDA lesioning of the basal ganglia, blocking P2X7 receptors has been shown to increase dopamine production, reduce abnormal rotational behavior, and prevent cell death.”
In addition, citations should be included in all tables.
4. It is recommended that some of the tables be integrated or displayed in a graphical form to make them clearer.
5. The authors should comprehensively summarize the limitations of the current research in each part.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsManuscript significantly improved.
