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

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.

Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease

“…Specifically, supplementing the maternal diet with additional choline (~4 times higher than found in normal lab chow) enhances memory and spatial cognition in offspring, a benefit that becomes more pronounced with aging [81, 82]. The improved spatial learning/memory in the offspring of choline-supplemented dams likely stems from concomitant changes in septohippocampal circuitry, including (i) the size and shape of MSN/VDB neurons, which correlate with memory function [83, 84]; (ii) altered Ach turnover and choline transporter expression in the septohippocampal circuit [85, 86]; (iii) changes in hippocampal neurogenesis, migration, gene expression, and neurotrophin levels [76, 87–90]; (iv) changes in dendritic fields and spine density in the dentate gyrus and CA1 region of the hippocampus [91]; (v) a lowered threshold for eliciting hippocampal long-term potentiation, a putative change underlying memory formation [92, 93]; (vi) alterations in Ach metabolizing enzymes [71, 94]; (vii) increased hippocampal responsiveness to cholinergic stimulation [94, 95]; and (viii) increased hippocampal progenitor cell proliferation and decreased apoptosis in these cells [55, 77, 87]. In sum, supplementing the maternal diet with additional choline during prenatal development produces lasting, organizational changes in structure and function of the septohippocampal system in ways consistent with the aforementioned improvement in memory function also produced by this early dietary manipulation.…”

“…In addition to the beneficial cognitive effects of MCS in normal rats and mice, this early dietary intervention provides lasting neuroprotective effects and attenuates cognitive impairment in a wide variety of rodent disease models including aging [73, 82, 97–99], prenatal alcohol exposure [100–102], epilepsy [103–105], excitotoxicity [106, 107], Rett syndrome [108–111], and notably, DS [74–76, 112]. …”

“…In this task, the animals must use extra-maze cues to locate a hidden escape platform at the end of one of the arms. Ts65Dn mice born to choline-supplemented dams exhibited lifelong improvements in spatial learning, performing nearly as well as their 2N littermates [74, 76] (Fig. 2A, B).…”

“…2A, B). In addition, MCS partially normalized adult hippocampal neurogenesis [76], evidenced by an increased number of doublecortin (DCX) containing cells, a marker for newly born neurons, within the dentate gyrus (Fig. 2C, D).…”

Changing Paradigms in Down Syndrome: The First International Conference of the Trisomy 21 Research Society

“…Choline is an essential nutrient during fetal development due to its role in acetyl choline production, cellular membrane formation, and epigenetic regulation. MCS produced a dramatic improvement in spatial cognition in aged Ts65Dn offspring, which correlated with hippocampal neurogenesis [Velazquez et al, 2013] as well as increased density and size of basal forebrain cholinergic neurons [Ash et al, 2014]. MCS also improved attention and emotional regulation in aged Ts65Dn mice [Moon et al, 2010].…”