Postnatal Growth Defects in Mice with Constitutive Depletion of Central Serotonin

Abstract

Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (−95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2 −/− mouse line and VMAT2 sert-cre mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2 pet1-cre ) in 5-HT raphe neurons leading to partial (−75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2 sert-cre mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2 sert-cre and Tph2 −/− mice, but not in the VMAT2 pet1-cre mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…Surprisingly, perinatal 5-HT deficiency only induces a reduction of barrel field organization without altering its general organization [177,207,208]. Nevertheless, further studies need to be carried since early reduction of 5-HT during embryonic development induces the emergence of altered behaviour [153].…”

“…For instance, mice deficient in Tph1 or Tph2 showed body weight reduction and delayed maturation of cortical layers [18,153,177]. Heterozygous embryos growing in null mutant Tph1 −/− mice showed an average of 30% reduction in proliferating cells (BrdU+) in the VZ after a 2 h pulse of BrdU administration, an analog of thymidine that is incorporated during the S phase of the cell cycle [18].…”

Serotonin controlling feeding and satiety

“…There are two isoforms of the enzyme; Tph1 which is predominantly expressed in the periphery, whereas Tph2 is predominantly expressed in the brain [38]. A Tph2 knockout in mice leads to retarded growth and lower body weight in early postnatal development [39,40]. An independent study found decreased food intake and bone mass in these mice [41] and the effects on body weight could possibly be gender dependent [42].…”

Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness

“…11 Previous studies 11,13 examined Tph2 KO mice at 4 to 16 weeks of age, whereas Lexicon's mice were examined at 18 through 83 weeks of age. Tph2 KO mice have a transient growth retardation starting a few days after birth and lasting through 4 months of age 18,19 and limited data from Lexicon's KO mouse screening analyses 16 support this finding. Low trabecular bone Modest skeletal phenotypes in adult Tph2 KO mice R Brommage et al mass in studies examining growing mice is possibly related to their small size.…”