Growth retardation and altered autonomic control in mice lacking brain serotonin

Abstract

Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2(-/-)) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2(-/-) mice. Moreover, Tph2(-/-) females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.

Fig. 1.

Serotonin system in the brain of Tph2-deficient mice. (A) Detection of serotonin (Middle panel) by immunofluorescence and of Tph2 and serotonin transporter (SLC6A4, SERT) transcripts by in situ hybridization (Upper and Lower panels, respectively) in the dorsal raphé (DR) of Tph2^−/− mice. CC, central canal. (B) Detection of serotonin (5-HT), its degradation product 5-hydroxyindoleacetic acid (5-HIAA), and the serotonin precursor tryptophan (Trp) in the DR by HPLC (representative HPLC-chromatogram, Upper panel and its quantification, Middle and Lower panels). ***, P < 0.001 Tph2^−/− vs. Tph2^+/+ and Tph2^+/−, Student's t test.

Fig. 2.

Growth retardation and postnatal lethality in Tph2-deficient mice. Representative photographs of 15-day-old FVB/N-Tph2-deficient (A) and 21-day-old C57BL/6-Tph2-deficient (B) mice. On both panels: Left, Tph2^−/− mouse; Right, Tph2^+/+ mouse from the same litter. Body weight (BW) development (mixed genetic background) (C) and survival (C57BL/6 genetic background) (D) of Tph2-deficient animals. Red line, Tph2^−/−; blue line, control mice. (E) IGF1 concentration in the serum of the Tph2-deficient animals (FVB/N-F4 genetic background) at different ages. Filled bars, Tph2^−/−; open bars, control mice. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 (Student's t test); and ^§, P < 0.0001 (Logrank test) Tph2^−/− vs. age-matched control mice; ^#, P < 0.05 (Student's t test) 4-month-old vs. 2-month-old Tph2^−/− mice.

Fig. 3.

Telemetric analysis of physiological parameters in Tph2-deficient mice. (A) Changes in the body temperature and locomotor activity after a challenge by a cold (4 °C) environment. Filled circles, Tph2^−/− (n = 7); open circles, control mice (n = 8) (4-month-old female mice, FVB/N F4 genetic background). Circadian variations in sleep (B), mean arterial blood pressure (BP) (C), heart rate (HR) in beats per minute (bpm) (D), and respiratory rate (RR) in breaths per minute (Bpm) (E) in Tph2-deficient 3-month-old female mice (FVB/N F4 genetic background). Bold line indicates nighttime. Filled circles, Tph2^−/− (n = 5), open circles, control mice (n = 5). *, P < 0.05; **, P < 0.01; and ***, P < 0.001 (Student's t test) Tph2^−/− vs. control mice at the same time point.