Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome

Neurobiol Dis. 2013 Oct;58:92-101. doi: 10.1016/j.nbd.2013.04.016. Epub 2013 Apr 30.

Abstract

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS.

Keywords: (2N Ch+); (2N); (BDNF); (BFCNs); (DAB); (DCX); (DG); (DS); (HSA21); (MCS); (MMU16); (NGF); (PB); (PND); (TBS); (TBST); (Ts65Dn Ch +); (Ts65Dn); 3/3′-diaminobenzidine tetrahydrochloride; Basal forebrain cholinergic neurons; Brain-derived neurotropic factor; Dentate gyrus; Disomic mice born to dams on a diet supplemented with additional choline; Disomic mice born to dams on a normal choline diet; Doublecortin; Down syndrome; Hippocampus; Human chromosome 21; Maternal choline; Maternal choline supplementation; Mouse chromosome 16; Nerve growth factor; Neurogenesis; Phosphate buffer; Postnatal day; Spatial learning; TBS with Triton X-100; Tris-buffered saline; Ts65Dn; Ts65Dn mice born to dams on a diet supplemented with additional choline; Ts65Dn mice born to dams on a normal choline diet.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Body Weight / genetics
  • Choline / administration & dosage*
  • Disease Models, Animal
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Down Syndrome / complications
  • Down Syndrome / genetics
  • Down Syndrome / pathology*
  • Female
  • Hippocampus / pathology*
  • Learning Disabilities / etiology
  • Learning Disabilities / prevention & control*
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Neurogenesis / genetics*
  • Neurogenesis / physiology
  • Neuropeptides / metabolism
  • Pregnancy / drug effects
  • Prenatal Exposure Delayed Effects
  • Prenatal Nutritional Physiological Phenomena / drug effects*
  • Space Perception / physiology*

Substances

  • DCX protein, human
  • Dcx protein, mouse
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Microtubule-Associated Proteins
  • Neuropeptides
  • Choline