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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39279505/
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. 2024 Oct 1;137(19):jcs262219.
doi: 10.1242/jcs.262219. Epub 2024 Oct 11.

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress

Monika Bijata  1 , Alexander Wirth  2 , Jakub Wlodarczyk  1 , Evgeni Ponimaskin  2
Affiliations

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress

Monika Bijata et al. J Cell Sci. .

Abstract

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. The serotonin receptors 5-HT1AR (also known as HTR1A) and 5-HT7R (also known as HTR7) have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here, we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we found that there was an increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found an increase in 5-HT7R expression exclusively in the PFC of resilient animals, whereas no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as the region exhibiting the highest abundance of 5-HT1AR-5-HT7R heterodimers. More importantly, upon chronic stress, the amount of heterodimers was significantly reduced only in PFC of anhedonic mice, whereas it was not affected in resilient animals. These results suggest an important role of brain-region-specific 5-HT1AR-5-HT7R heterodimerization for establishing depressive-like behaviour and for development of resiliency.

Keywords: 5-HT1AR; 5-HT7R; Chronic stress; Heterodimerization; Serotonin receptors.

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Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Developmental dynamics of 5-HT1AR and 5-HT7R expression in the PFC, HP and RN. (A) Representative western blot showing 5-HT1AR, 5-HT7R and GAPDH in the PFC, HP and RN at postnatal day 2 (P2), 12 (P12) and 90 (P90). (B,C) Quantification of the 5-HT1AR (B) and 5-HT7R (C) expression in HP, PFC and RN in P2, P12 and P90 (nmice=6). (D) Relative expression of mRNA encoding 5-HT1AR and 5-HT7R in PFC, HP and RN in P2, P12 and P90 (nmice=3). The data are presented as the mean±s.e.m. *P<0.05; **P<0.01; ***P<0.001 [one-way ANOVA test followed by Tukey's multiple comparisons test (B,C); two-tailed unpaired t-test (D)]. Scheme was prepared using the BioRender software.
Fig. 2.
Fig. 2.
Behavioural evaluation of depressive-like behaviour of ANH, RES and CTR animals following CUS. (A) Schematic view of the experimental design of the CUS model (prepared using the BioRender software). SPT, sucrose preference test; FST, forced swimming test, W – body mass (weight) measurement. (B) Relative changes of initial body mass after CUS. (C) Results of SPT after CUS. (D) Results of FST after CUS in CTRL, ANH and RES animals. The data are presented as the mean±s.e.m. (nmice=9). *P<0.05; **P<0.01; ***P<0.001 [Brown–Forsythe ANOVA test followed by Tamhane's T2 multiple comparisons test (B); one-way ANOVA test followed by Tukey's multiple comparisons test (C,D)].
Fig. 3.
Fig. 3.
Expression of 5-HT1AR and 5-HT7R in the PFC, HP and RN following CUS. (A) Representative western blot showing 5-HT1AR, 5-HT7R and GAPDH expression in the PFC, HP and RN in CTRL, ANH and RES mice. Quantification of the 5-HT1AR (B) and 5-HT7R (C) expression in PFC, HP and RN of CTRL, ANH and RES mice (nmice=3). The data are presented as the mean±s.e.m. *P<0.05; **P<0.01; ***P<0.001 (one-way ANOVA test followed by Tukey's multiple comparisons test).
Fig. 4.
Fig. 4.
Expression of 5-HT1AR and 5-HT7R in different brain areas. Schematic presentation of brain regions analysed based on Allen Mouse Brain Common Coordinate Framework version 3 (Bakker et al., 2015) (on the left). PFC, prefrontal cortex; HP, hippocampus; RN, raphe nuclei. Representative immunohistochemical stainings from three repeats at P90 with DAPI (blue), 5-HT1AR (green) and 5-HT7R (red) are shown on the right. White squares mark regions enlarged at the bottom. Scale bars: 50 µm (PFC); 20 µm (HP and RN).
Fig. 5.
Fig. 5.
Heterodimerization of 5-HT1AR and 5-HT7R in RN. (A) An overview and an enlargement of immunohistochemical staining of 5-HT positive neurons (green) in the RN. DAPI is shown in blue. In addition, inset ii shows PLA signal (red). Scale bars: 100 µm (main image), 10 µm (inset i); 5 µm (inset ii). (B) Quantification of PLA-positive blobs per cell in RN of CTRL, ANH or RES animals. (C) Quantification of PLA-positive blobs restricted to 5-HT-positive cells in RN of CTRL, ANH or RES animals. The data are presented as the mean±s.e.m. (nmice≥5; CTRL=7, ANH=6, RES=5). Kruskal–Wallis test with Dunn's multiple comparison.
Fig. 6.
Fig. 6.
Heterodimerization of 5-HT1AR and 5-HT7R in PFC and HP. (A) Representative images of PLA results in the PFC (upper panel) and dentate gyrus of the HP (lower panel) of CTRL, ANH or RES animals. Scale bars: 10 μm. (B) Quantification of PLA-positive blobs per cell in both brain regions of CTRL, ANH or RES animals (nmice≥5; CTRL=7, ANH=6, RES=5). The data are presented as the mean±s.e.m. **P<0.01; ***P<0.001 (Kruskal–Wallis test with Dunn's multiple comparison).
Fig. 7.
Fig. 7.
Graphical summary of the present study. Levels of 5-HT1AR–5-HT7R heterodimerization are reduced in the PFC of ANH animals, whereas in RES animals it remains at the same level as in control animals. This could be explained by increased expression of 5-HT7R in the PFC of RES mice. Scheme was prepared using the BioRender software.
See this image and copyright information in PMC

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