Specific Disruption of Hippocampal Mossy Fiber Synapses in a Mouse Model of Familial Alzheimer's Disease

Anirvan Ghosh,Mark H Ellisman,Joseph K Antonios,Tara Raam,Scott A Wilke,Edward H Koo,Eric A Bushong,Sergio T Ferreira

doi:10.1371/journal.pone.0084349

Anirvan Ghosh, Mark H Ellisman + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0084349

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Journal: PLoS ONE	Publication Date: Jan 13, 2014
Citations: 27	License type: CC BY 4.0

Affiliation: University of California, San Diego, Roche (Switzerland)

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by early deficits in learning and memory leading to eventual disruption of higher cognitive processes [1]
The mossy fiber (MF) bouton (MFB) is considerably larger than typical excitatory presynaptic terminals and synapses with large, multi-headed CA3 dendritic spines known as thorny excrescences (TEs) (Figure 1B) [32]
There were no obvious differences in the ultrastructural organization of synapses from WT and familial AD (FAD) mutants, MFB contours appeared to be decreased in density and cross-sectional area (Figure 1C–H)

Summary

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by early deficits in learning and memory leading to eventual disruption of higher cognitive processes [1]. Mouse models of familial AD (FAD), with mutations in human amyloid precursor protein (APP) lead to overproduction of Ab with synaptic dysfunction and learning deficits, which precede plaque formation [5,6,7,8,9]. While analysis of synapse structure in FAD mutant mice has been limited, studies suggest a reduced density of dendritic spines in vitro [11] and in vivo [12,13,14]. Despite this recent recasting of AD in light of synapse dysfunction, there has been limited investigation of how specific synaptic populations are affected in the course of the disease. Investigation of specific microcircuits at the level of electron microscopy offers the best hope of understanding the synaptic basis of functional deficits

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