Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.
The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement.
Belichenko
Pavel V
PV
Department of Neurology and Neurological Sciences and the Center for Research and Treatment of Down Syndrome, Stanford University Medical Center, 1201 Welch Road, Stanford, California 94305-5489, USA. pavel_belichenko@yahoo.com
Masliah
Eliezer
E
Kleschevnikov
Alexander M
AM
Villar
Angela J
AJ
Epstein
Charles J
CJ
Salehi
Ahmad
A
Mobley
William C
WC
D000818:Animals; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D049229:Dendritic Spines / Q000648:ultrastructure*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009044:Motor Cortex / Q000473:pathology / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000648:ultrastructure; D012016:Reference Values; D013003:Somatosensory Cortex / Q000473:pathology / Q000648:ultrastructure; D013569:Synapses / Q000648:ultrastructure*