Journal
JOURNAL OF COMPARATIVE NEUROLOGY
Volume 505, Issue 4, Pages 352-362Publisher
WILEY
DOI: 10.1002/cne.21485
Keywords
amyloid precursor protein; presenilin 1; drebrin; excitatory synapses; electron microscopic immunocytochemistry; ultrastructure
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Funding
- NEI NIH HHS [P30 EY013079, R01 EY 13145, R01 EY013145, P30 EY013079-109003, 1P30 EY 13079, R01 EY013145-04] Funding Source: Medline
- NINDS NIH HHS [R01 NS041091, R01 NS041091-04, R01 NS 41091, R25 NS080686] Funding Source: Medline
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Mice with knock-in of two mutations that affect beta amyloid processing and levels (2xKI) exhibit impaired spatial memory by 9-12 months of age, together with synaptic plasticity dysfunction in the hippocampus. The goal of this study was to identify changes in the molecular and structural characteristics of synapses that precede and thus could exert constraints upon cellular mechanisms underlying synaptic plasticity. Drebrin A is one protein reported to modulate spine sizes and trafficking of proteins to and from excitatory synapses. Thus, we examined levels of drebrin A within postsynaptic spines in the hippocampus and entorhinal cortex. Our electron microscopic immunocytochemical analyses reveal that, by 6 months, the proportion of hippocampal spines containing drebrin A is reduced and this change is accompanied by an increase in the mean size of spines and decreased density of spines. In the entorhinal cortex of 2xKI brains, we detected no decrement in the proportion of spines labeled for drebrin A and no significant change in spine density at 6 months, but rather a highly significant reduction in the level of drebrin A immunoreactivity within each spine. These changes are unlike those observed for the somatosensory cortex of 2xKI mice, in which synapse density and drebrin A immunoreactivity levels remain unchanged at 6 months and older. These results indicate that brains of 2xKI mice, like those of humans, exhibit regional differences of vulnerability, with the hippocampus exhibiting the first signatures of structural changes that, in turn, may underlie the emergent inability to update spatial memory in later months.
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