α/β-Hydrolase domain-containing 6 (ABHD6) accelerates the desensitization and deactivation of TARP γ-2-containing AMPA receptors

Reviewer #1 (Public Review):

Summary:

This research sheds light on the nuanced role of ABHD6 in the regulation of AMPARs, highlighting its interaction with TARP γ-2 as a critical factor in modulating receptor-gating kinetics. It is crucial to understand that while ABHD6 alone does not alter AMPAR kinetics, its presence alongside TARP γ-2 leads to accelerated deactivation and desensitization of AMPARs, impacting synaptic transmission dynamics.

Strengths:

Important findings in the research include:
- ABHD6 does not affect the gating kinetics of GluA1 and GluA2(Q) homomeric receptors independently.
- In the presence of TARP γ-2, ABHD6 accelerates deactivation and desensitization of these receptors, regardless of their splicing or editing isoforms.
- The effect is consistent for both homomeric GluA1 and GluA2(Q) receptors and heteromeric GluA1i/GluA2(R)i-G receptors.
- The recovery from desensitization of GluA1 with the flip splicing isoform is slowed by ABHD6 in the presence of TARP γ-2.

Weaknesses:

However, the study focuses on specific receptor subunits and isoforms, which may not fully represent the diversity of AMPAR compositions found in vivo (e.g. though the authors have claimed that TARP γ-2 failed to increase GluA3-induced currents significantly, the effect on GluA4 or the explanation was missing). Further research is needed to explore the implications of these findings in more complex neuronal environments.

Reviewer #2 (Public Review):

Summary:

Cong et al. investigated the regulatory effects of ABHD6 on AMPARs. The authors performed adequate electrophysiology recordings to show the exact pattern of this regulation and covered major critical points.

Strengths:

The authors have performed high-quality ephys recordings and examined all potential regulatory aspects of ABHD6 on AMPARs. This is important to understand the AMPAR functions.

Weaknesses:

(1) The authors discussed CNIH-2 extensively from line 92-110 in the introduction, however, they did not perform related experiments. I suggest they move this part to the discussion where they also discussed the roles of CNIH.
(2) The authors need to report the "n" for all the experiments they have presented in this manuscript. How many cells were recorded in each condition? How many batches? This information has to be in all of the figure legends, but it is missing except Fig. 4.
(3) One question is what the physiological meanings of this regulatory effect are. The authors may consider adding some discussions.
(4) About statistics. The authors need to add more details and make sure their statistics sound. For example, they also need to check the equality of variances. In their Table EVs, where the P values are reported, the authors need to report which statistics they have used, one-way ANOVA, K-W test, or others, and the exact post-hoc test type for each comparison. For one-way ANOVA, report the F values simultaneously with the P values in all figure legends.
(5) Fig. 3J, the authors need to correct the label of the Y axis. It is shifted.