Modulation of large rhythmic depolarizations in human large basket cells by norepinephrine and acetylcholine

Rhythmic brain activity is critical to many brain functions and is sensitive to neuromodulation, but so far very few studies have investigated this activity on the cellular level in vitro in human brain tissue samples. This study reveals and characterizes a novel rhythmic network activity in the human neocortex. Using intracellular patch-clamp recordings of human cortical neurons, we identify large rhythmic depolarizations (LRDs) driven by glutamate release but not by GABA. These LRDs are intricate events made up of multiple depolarizing phases, occurring at ~0.3 Hz, have large amplitudes and long decay times. Unlike human tissue, rat neocortex layers 2/3 exhibit no such activity under identical conditions. LRDs are mainly observed in a subset of L2/3 interneurons that receive substantial excitatory inputs and are likely large basket cells based on their morphology. LRDs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators that affect network dynamics. NE increases LRD frequency through β-adrenergic receptor activity while ACh decreases it via M4 muscarinic receptor activation. Multi-electrode array recordings show that NE enhances and synchronizes oscillatory network activity, whereas ACh causes desynchronization. Thus, NE and ACh distinctly modulate LRDs, exerting specific control over human neocortical activity.


Modulation of Large Rhythmic Depolarizations in Human Large Basket Cells by Norepinephrine and Acetylcholine
This article by Yang et al. is a revised version of an article I previously reviewed for Nature Communication.This new version is not very different from the previous one, but the authors have made some improvements and corrections that address the main remaining issues as much as possible.As a result, my assessment of the current version remains very similar to my initial assessment: 1) The experiments and data analysis are well conducted, and I have no concerns about the validity and quality of the data.Although not very innovative and classic in its design, this study presents solid and convincing results.In particular, I find the detailed comparison of the physiology and anatomy of LRD+ and LRD-interneurons remarkable, and overall, the results are novel and original.
2) Two major limitations were raised throughout the review process, namely i) the lack of mechanistic understanding of the generation of these large rhythmic depolarizations (LRDs) and ii) the possibility that LRDs are merely pathological activity found in cortical circuits affected by epileptic activity.However, I have the impression that both reviewers and authors agreed that these points are probably not easy to address experimentally due to the low probability of these events and the difficulty of obtaining tissue samples from human patients.These limitations should therefore be clearly mentioned and discussed in the article, which is now the case.
The overall relevance and significance of this study remains a matter of debate.Are LRDs primarily an epiphenomenon associated with pathological cortical circuits, or are they important network events that have a functional impact on human brain function?Future studies will be needed to answer these questions, but I think the results reported in this article would be of interest to the growing community of neuroscientists working on human cortical circuits at the cellular level.
One minor point: I'm not convinced that LRDs are truly rhythmic in their occurrence.In fact, it seems rather that LRDs show great variability in their inter-event intervals (see figure 1c).Consequently, I would like to suggest replacing the term "rhythmic" with "recurrent".
Reviewer #2 (Remarks to the Author): No further comments.

Response to Reviewer #1!s comments:
Reply: We thank the reviewer for the support of publication.

This article by Yang et al. is a revised version of an article I previously reviewed for Nature
Communication.This new version is not very different from the previous one, but the authors have made some improvements and corrections that address the main remaining issues as much as possible.As a result, my assessment of the current version remains very similar to my initial assessment: 1) The experiments and data analysis are well conducted, and I have no concerns about the validity and quality of the data.Although not very innovative and classic in its design, this study presents solid and convincing results.In particular, I find the detailed comparison of the physiology and anatomy of LRD+ and LRD-interneurons remarkable, and overall, the results are novel and original.
2) Two major limitations were raised throughout the review process, namely i) the lack of mechanistic understanding of the generation of these large rhythmic depolarizations (LRDs) and ii) the possibility that LRDs are merely pathological activity found in cortical circuits affected by epileptic activity.However, I have the impression that both reviewers and authors agreed that these points are probably not easy to address experimentally due to the low probability of these events and the difficulty of obtaining tissue samples from human patients.These limitations should therefore be clearly mentioned and discussed in the article, which is now the case.
The overall relevance and significance of this study remains a matter of debate.Are LRDs primarily an epiphenomenon associated with pathological cortical circuits, or are they important network events that have a functional impact on human brain function?Future studies will be needed to