Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease.
The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control - they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease.
Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
Scott A
SA
Wilke
Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
Tara
T
Raam
Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
Joseph K
JK
Antonios
National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California, United States of America.
Eric A
EA
Bushong
Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
Edward H
EH
Koo
National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California, United States of America.
Mark H
MH
Ellisman
Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America ; Neuroscience Discovery and Translational Area, pRED, F. Hoffmann-La Roche, Basel, Switzerland.
Anirvan
A
Ghosh
D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D013569:Synapses / Q000473:pathology* / Q000648:ultrastructure