Serotonin receptor HTR6 mediates DR-induced memory enhancement.

(A, B) Memory indexes of mice on different diets (AL, DR, and DR plus carb, protein, fat, Tyr, Trp, Cys, or Glu to a level equivalent to AL [n = 10–11 mice per group]) for 8 weeks. (C) Memory indexes of AL and DR mice after IP injection of saline or fenfluramine (n = 12 mice per group). (D–H) Serotonin and 5-HIAA levels (D), 5-HIAA/5-HT ratios (E), serotonin receptor mRNA levels (F), and representative western blots and quantitative protein expression levels of HTR6 (G, H) in hippocampal tissues of AL and DR mice (n = 5–6 per group). (I) An elevated level of serum corticosterone was detected in DR mice compared to the AL group (n = 7–9 mice per group). (J–K) HTR6 mRNA expression in mouse hippocampal tissues (n = 5 per group) (J) and memory indexes of mice (K) receiving 6 weeks of vehicle (“Veh”) or corticosterone (“Cort”) treatment in the drinking water (n = 11 mice per group). (L, M) Memory indexes of AL and DR mice after IP injection of HTR6-specific agonist (WAY) (L) and HTR6-specific antagonist (SB, n = 10–12 mice per group) (M). (N) HTR6 KO mice have normal food intake (n = 10–11 cages per group). (O-S) The body weight change (O), representative moving path (P, Q), and travel distance during the open field test (R) and calculated memory indexes during the NOR test (S) of WT and HTR6 KO mice after 8 weeks of dietary manipulations (AL, DR, and DR plus Trp to a level equivalent to AL [n = 9–14 mice for each group]). (T–V) Representative moving path (T), travel distance during the open field test (U), and calculated memory indexes during the NOR test (V) of HTR6 KO DR mice after IP injection of saline or fenfluramine (n = 5–6 mice per group). Data are presented as mean ± SEM. *P P P t test, one-way ANOVA, or two-way ANOVA with Fisher’s LSD post hoc test. #P P S1 Data. 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; AL, ad libitum; carb, carbohydrate; Cys, cysteine; DR, dietary restriction; Glu, glutamate; HTR, 5-hydroxytryptamine receptor; IP, intraperitoneal; KO, knockout; LSD, least significant difference; NOR, novel object recognition; SB, SB 399885 hydrochloride; Trp, tryptophan; Tyr, tyrosine; WAY, WAY 208466 dihydrochloride; WT, wild type.