Figure 1. Forebrain suppression of pyramidal 5-HT_1A heteroreceptors results in a depression-like phenotype.

(A) tTS system cartoon. Top: Mice homozygous for the Htr1a^tetO allele and possessing one copy of the α-CaMKII–tTS transgene express 5-HT_1A receptors in normal patterns when maintained on doxycycline (DOX). Bottom: In the absence of DOX, transcription of 5-HT_1A is suppressed in the forebrain but not in the raphe nucleus (RN). (B) No differences were detected between Hetero-KO mice and controls in total path (ANOVA for main effect of group: F_(1,26)=0.659; p=0.4242) or (C) % center distance in the open-field (ANOVA for main effect of group: F_(1,26)=0.322; p=0.5754; n=10–18/group). (D) No differences were detected between groups in time spent in the open arms of the elevated-plus maze (ANOVA for main effect of group: F_(1,26)=0.036; p=0.8515; n=10–18/group). (E) Hetero-KO mice displayed increased latency in the NSF (Kaplan-Meier survival analysis with Mantel-Cox: p<0.01; n=10–18/group). (F) No differences were detected between groups in the fear-conditioning paradigm. Percent time freezing at baseline (ANOVA for main effect of group: F_(1,17)=0.213; p=0.6505) and during context test (ANOVA for main effect of group: F_(1,17)=0.021; p=0.8876). (G) Percent time freezing in novel context in the absence and presence of the tone (ANOVA for main effect of group: F_(1,17)=0.056; p=0.8166; n=8–11/group). (H) Hetero-KO mice displayed decreased cookie consumption (ANOVA repeated measures for main effect of group: F_(1,23)=37.243; p<0.0001; for main effect of time: F_(1,3)=3.345; p<0.05; n=8–17/group) and (I) decreased sucrose preference compared to controls (Two-way ANOVA repeated measures time x group interaction for choice testing days (5–8): F_(3,54)=10.065; p<0.0001; main effect of group: F_(1,18)=96.561; p<0.0001; n=9–11/group). (J) Hetero-KO mice displayed decreased mobility compared to controls in a 2 day FST (ANOVA for main effect of group: Day 1, F_(1,17)=6.389; p<0.05; Day 2, F_(1,17)=47.447; p<0.01; n=8–11/group). (K) No difference in CORT levels at the onset of both the light and the dark phase was detected between groups (ANOVA for main effect of group: AM: F_(1,14)=0.047; p=0.8309; PM: F_(1,16)=0.001; p=0.9758; n=8–9/group). (L) Hetero-KO mice display an enhanced CORT response to a forced-swim stressor compared to controls (ANOVA for main effect of group: F_(1,10)=7.306; p=0.0222; n=6/group). Male mice were tested starting at 12–14 weeks of age. Data are represented as mean±SEM. *p≤0.05, **p<0.01. See also Figure S1 and S2.