Benefits Of Maternal Choline Supplementation In A Mouse Model Of Down Syndrome: Elucidation Of Underlying Neural Mechanisms

Abstract

BENEFITS OF MATERNAL CHOLINE SUPPLEMENTATION IN A MOUSE MODEL OF DOWN SYNDROME: ELUCADATION OF UNDERLYING NEURAL MECHANISMS Ramon Velazquez Jr., Ph. D. Cornell University Down syndrome (DS) is the most common known cause of intellectual disability (ID), affecting 1 in 800-1000 births. This disorder is caused by triplication of human chromosome 21(HSA21) due to nondisjunction during meiosis. In addition to ID, individuals with 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). Although there are currently no effective treatments for either the ID or dementia seen in this disorder, it is hoped that the recent development of murine models of this disease will aid in elucidating the pathogenic mechanisms and testing potential therapies. The Ts65Dn mouse model of DS survives to adulthood and exhibits key features of this disorder, notably impairments in learning, attention, and memory, as well as deficient ontogenetic neurogenesis and degeneration of basal forebrain cholinergic neurons (BFCNs) in the medial septum (MS). The overarching goal of the present thesis was to use this mouse model to study the role of cholinergic atrophy in the age-related cognitive decline seen in DS (Chapter 3), and to test the effectiveness of one promising therapy for DS (Chapter 1 and 2): maternal choline supplementation (MCS). Our studies revealed that Ts65Dn mice exhibit attentional dysfunction as early as 3 months of age, which becomes more pronounced with aging. Moreover, assessment of cholinergic neurons in the nucleus basalias of meynert/substantia innominata revealed a reduced density of these neurons in both young and old trisomic mice (relative to 2N), but no age-related changes in the count, density or size of these neurons was observed with aging as is commonly believed. Our subsequent studies using MCS revealed that the Ts65Dn offspring of dams supplemented with additional choline during pregnancy and lactation exhibited improvements in spatial cognition, relative to Ts65Dn offspring of dams on the control diet. In addition, MCS significantly increased adult neurogenesis of the trisomic offspring and offered protection to BFCNs in the MS. These results provide exciting new evidence that MCS may represent a safe and effective treatment approach for expectant mothers carrying a DS fetus, as well as a possible means of BFCN neuroprotection during aging for the population at large.