Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Ling-Ling Teng; Guan-Ling Lu; Lih-Chu Chiou; Wei-Sheng Lin; Ya-Yun Cheng; Tai-En Hsueh; Yi-Ching Huang; Nai-Hsuan Hwang; Jin-Wei Yeh; Ruey-Ming Liao; Shou-Zen Fan; Jui-Hung Yen; Tsai-Feng Fu; Ting-Fen Tsai; Ming-Shiang Wu; Pei-Yu Wang

doi:10.1371/journal.pbio.2007097

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

PLoS Biol. 2019 Mar 18;17(3):e2007097. doi: 10.1371/journal.pbio.2007097. eCollection 2019 Mar.

Authors

Ling-Ling Teng¹, Guan-Ling Lu², Lih-Chu Chiou^{1

2

3

4}, Wei-Sheng Lin^{1

5}, Ya-Yun Cheng¹, Tai-En Hsueh¹, Yi-Ching Huang¹, Nai-Hsuan Hwang^{1

6}, Jin-Wei Yeh¹, Ruey-Ming Liao⁶, Shou-Zen Fan⁷, Jui-Hung Yen⁸, Tsai-Feng Fu⁹, Ting-Fen Tsai¹⁰, Ming-Shiang Wu¹¹, Pei-Yu Wang^{1

3

12

13

14}

Affiliations

¹ Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.
⁴ Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan.
⁵ Department of Pediatrics, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁶ Institute of Neuroscience, National Cheng-Chi University, Taipei, Taiwan.
⁷ Department of Anesthesiology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
⁸ Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, United States of America.
⁹ Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan.
¹⁰ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
¹¹ Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
¹² Center for Systems Biology, National Taiwan University, Taipei, Taiwan.
¹³ PhD Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.
¹⁴ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Abstract

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / blood
Animals
Blotting, Western
Corticosterone / blood
Electrophysiology
Glucose Tolerance Test
Hippocampus / cytology
Hippocampus / metabolism
Long-Term Potentiation / physiology
Male
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Memory / physiology*
Mice
Mice, Inbred C57BL
Neurons / cytology
Neurons / metabolism
RNA, Messenger / metabolism
Receptors, Serotonin / genetics
Receptors, Serotonin / metabolism*
Serotonin / blood
Signal Transduction / genetics
Signal Transduction / physiology

Substances

RNA, Messenger
Receptors, Serotonin
serotonin 6 receptor
Serotonin
Mechanistic Target of Rapamycin Complex 1
3-Hydroxybutyric Acid
Corticosterone

Grants and funding

Ministry of Science and Technology, Taiwan (grant number MOST103-2320-B-002-031, MOST105-2410-H-002-050-MY2, and MOST107-2410-H-002-118). Received by PYW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministry of Science and Technology, Taiwan (grant number MOST104-2923-B002-006-MY3 and MOST107-2321-B-002-010). Received by LCC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Taiwan University Hospital (grant number UN105-026). Received by MSW and PYW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Taiwan University Hospital Yunlin branch (grant number NTUHYL106.X011). Received by WSL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Health Research Institutes, Taiwan (grant number NHRI-EX107-10733NI). Received by LCC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.