| Down syndrome (DS) is a genetic and developmental condition caused by trisomy of human chromosome 21 that occurs approximately 1 in 600 - 1000 live births, and is detectable in the second and third trimesters. DS individuals experience mental retardation (MR) and early incidence of Alzhiemer's disease (AD)-related neuropathology, including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Clinical presentation of a dementia similar to AD presents in an estimated 50 % of DS individuals over the age of 50 yrs and 75 % over the age of 60 yrs. Currently there is no viable treatment option for either the MR or early AD in DS, despite the advantage of early detection. In a mouse model with segmental trisomy for many genes orthologous to those on human chromosome 21, Ts65Dn, behavioral deficits and age-related degenerative changes in the BFCN system are seen. To explore the possible benefit of early nutritional supplementation with choline in Ts65Dn mice, we examined the BFCN system in Ts65Dn mice and disomic littermates (2N) supplemented with choline from conception to weaning via maternal diet (5.1 mg/ kg choline chloride in dry food, AIN-76A, Dyets, Inc.) with an unsupplemented, choline-controlled diet (1.1 mg/kg) for controls. Using choline acetyltransferase (ChAT) and the neurotrophin receptor p75 NTR as markers, the BFCN system was analyzed for BFCN number, size, density, region area, and hippocampal innervation in four cohorts of mice: (1) separate male and female groups of Ts65Dn and 2N mice at 5 - 8 mos born to and reared by dams fed a standard diet, (2) mixed male and female groups of Ts65Dn and 2N mice at 4 - 8 mos born to and reared by dams fed either a choline-supplemented or a choline-controlled, unsupplemented diet, (3) male Ts65Dn and 2N mice at 14 - 18 mos born to and reared by dams fed either a choline-supplemented or a choline-controlled, unsupplemented diet, and (4) male Ts65Dn and 2N mice at 6 - 8 and 14 - 18 mos born to and reared by dams fed a standard diet. We found little difference between males and females in the BFCN subregions medial septum/vertical limb of the diagonal band (MS/VDB) and horizontal limb of the diagonal band (HDB), but decreased BFCN number and size in the subregion nucleus basalis of Meynert/substantia innominata (NBM/SI) of female Ts65Dn mice. On the whole, differences seen between genotypes and with aging were subregion and measure-specific; although, Ts65Dn mice consistently had larger BFCN region areas and increased hippocampal ChAT intensity compared with 2N mice. Perinatal choline supplementation normalized some genotype differences seen in Ts65Dn mice but left others unchanged; and, perinatal choline supplementation globally increased 2N hippocampal ChAT-positive fiber innervation, but did not alter already elevated levels in Ts65Dn mice. The present series of studies coupled with a large body of literature on the benefits of early choline supplementation for behavior in disomic rodents, demonstrates that perinatal choline supplementation is a likely promising treatment strategy to counter the MR and early-onset AD-like degenerative changes that characterize DS. Additionally, based on differences we observed in the BFCN system between male and female mice, sex differences in the amount of choline supplemented and for the benefit received from early choline supplementation may exist, warranting different treatment strategies for males and females. |
