Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability
(ID) and early onset of Alzheimer’s disease (AD) neuropathology including hippocampal cholinergic
projection system degeneration. Here we determined the effects of age and maternal choline
supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and
14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an
aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a
choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally
tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of
choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort.
ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared
with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in
Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal
cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial
memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced
by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational
approaches in human DS.
Keywords: Aging, cholinergic, Down syndrome, hippocampus, intellectual disability, maternal choline supplementation,
spatial memory, Ts65Dn mice.
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