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

Maternal Choline Supplementation Improves Spatial Learning and Adult Hippocampal Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

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Free PMC article

Maternal Choline Supplementation Improves Spatial Learning and Adult Hippocampal Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

Ramon Velazquez et al. Neurobiol Dis. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Mean (+/− SE) errors in the Hidden Platform task, (A) plotted as a function of session block (3 sessions per block) and (B) averaged across the 15 sessions: MCS improved performance of the adult Ts65Dn offspring in the Hidden Platform task of the radial arm water maze, a hippocampal-dependent task. * p ≤ 0.01.
Figure 2
Figure 2
Mean (+/− SE) errors in the Visible Platform task across the 6 sessions of testing. The groups did not differ in their performance in the Visible Platform task.
Figure 3
Figure 3
DCX-positive cells in the subgranular zone and granular cell layer of the hippocampus across different treatment groups. Adult hippocampal neurogenesis is deficient in Ts65Dn mice (C, D) compared to 2N littermates (A, B). Choline supplementation partially normalized adult neurogenesis in Ts65Dn mice (G, H). No effect of maternal choline supplementation was observed in 2N mice (E, F). h = hilus.
Figure 4
Figure 4
Mean (+/− SE) number of DCX-positive cells in the dentate gyrus of the hippocampus. Unsupplemented Ts65Dn mice expressed significantly fewer DCX- positive cells than the 2N mice (P < 0.0001). Maternal choline supplementation significantly increased the number of DCX positive cells for the Ts65Dn mice (P < 0.001). * p < 0.001.
Figure 5
Figure 5
Correlation between mean errors in the water maze and DCX-positive cell number, showing the line of best fit. A negative correlation was seen between mean errors in the water maze and DCX-positive cell number in the dentate gyrus (rs(41) = −.470, P < 0.001); i.e. as hippocampal neurogenesis increased, the number of errors decreased.

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