The Role of Lactylation in Mental Illness: Emphasis on Microglia

Round 1

Reviewer 1 Report

The present paper from Sfera and colleagues is a Perspective focused on three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and aryl hydrocarbon receptor, authors also discuss potential interventions for restoring microglial homeostasis. My general impression is positive: the topics are interesting, covered with adequate depth and sustained by numerous references.

Anyway I have some constrains:

- Please add at the beginning of the paragraphs of the three anti-inflammatory microglial systems (lactate, OXT, and AhR) a description summarizing the characteristics of the signalling pathways activated by these receptors (the type/family of receptors, the subtypes of receptor if any, the second messengers etc.)

- Figures are not referenced in the text, please amend.

- Figure 1: in general this figure is poor of details, the glucose/lactate pathway appears out of the neuron without any other detail and also the interaction between the lactate molecules and histones is poorly described. Please amend.

- Figure 2: please add “resting microglia” on the blue cell and change “Moesin” with “moesin receptor” on the cell membrane. The caption of the figure is lacking description of Perforin and IL-17.

- References should be in squared brackets.

- Sentences like: “This section will describe...” (line 96) or “... as it will be revealed in this section” (line 183)  or “In this section, we ...” (line 309) are not necessary. Please remove.

- In the paper there are numerous acronyms, please a section at the enf of the manuscript with the elencation of all the acronyms used and their meanings. Add also an acronym for Schizophrenia, that appers several time in the text.

- line 157: plese change the title “Kla and microbes” with a more descriptive title.

- line 180: “Oxytocin-Oxytocin receptor signaling, a second microglial anti-inflammatory system” is a title? If so put in bold type.

- In my opinion in the chapter “Aryl hydrocarbon receptor and innate lymphoid cells” the paragraph from line 249 to line 264 should be moved at the beginning of the chapter.

- TABLE 1. Please format the Table in a better way, words are misaligned. In my opinion the underground colour should be white instead of yellow (also in TABLE 2).

- The organization of the three paragraph (lactate, OXT, and AhR) and the sub-paragraph of the Chapter “Potential therapeutic strategies” is not clear to the reader, please change the font of paragraph and sub-paragraph.

- Line 337, 343, 368, 375, 380, 396: the meaning of the code number inside the brackets should be clearly specified.

Author Response

Please see 

Author Response File: Author Response.docx

Reviewer 2 Report

Major comments

In this study, the authors tried to describe novel implications of metabolic changes in the pathogenesis of neuropsychiatric disorders. This is an interesting Perspective article with high originality; however, there are issues of serious concerns.

1.         Throughout the manuscript

Overall, a topic description is severely unbalanced. Abstract and Introduction sections describe microglia-related issues. However, the main text focuses on the pathological roles of other cells, such as innate lymphoid cells, rather than those of microglia, in the development and progression of neuropsychiatric disorders. In this respect, the Title, Abstract, Introduction, title of each section, and Conclusions do not appropriately reflect the contents described in the main text. There is the need to reconstitute the manuscript for consistency.

2.         Anti-inflammatory roles of microglia

The authors state that aberrant elimination of resting/anti-inflammatory microglia would be implicated in the pathogenesis of neuropsychiatric disorders (Figure 2 and the relevant description); however, microglia are innate immune cells with multiple functions, and anti-inflammatory property is just one of them. To support Conclusion 1 (lines 437–438), the authors should provide much more existing literatures that report the significance of anti-inflammatory roles of microglia in preventing the development of the disorders.

3.         Roles of lactate

The sentence “Although lactate is neuroprotective… (line 104)” is appeared suddenly. I suggest that the authors describe the neuroprotective effects of lactate in more detail.

4.         Format for the article

It was hard to follow the story due to inappropriate format. I suggest that section, subsection, or subsubsection should be assigned to the description on the lines 180, 311, 319, 327, 344, 350, 369, and 382, whereas that on the line 390 might be deleted.

5.         Aryl hydrocarbon receptor (AhR)

AhR-related sections (lines 226–280 and 382–407) rarely include the description regarding microglia, as raised in the Comment 1. This manuscript needs the reconstitution.

Minor comments

1.         Abbreviation (NKCs on the line 83) must be spelled out completely on initial appearance in text.

Author Response

Please see attached

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Dear Authors,

I received the revised form of the manuscript. Thank you for providing the corrections suggested, there is only a mistake in Fig. 1. Please change the word "translation" into "transcription" next to the arrow that goes from DNA to RNA.

After this correction the paper is suitable to be accepted for publication.

Kind regards

Author Response

Figure 1 corrected

Reviewer 2 Report

The revised manuscript has greatly been improved.

Author Response

Figure 1 corrected.