Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses

Marta Maglione,André Zeug,Bence Rácz,Laura Moreno-Velasquez,Franziska E Müller,Sebastian J Hofer,Frank Madeo,David Toppe,Dietmar Schmitz,Nikolaus Maier,Eva Michael,Evgeni Ponimaskin,Alexander Stumpf,Tobias Eisenberg,Rosanna P Sammons,Tanja Maritzen,Alexander Wirth,Volker Haucke,Gaga Kochlamazashvili,Stephan J Sigrist

doi:10.1038/s41598-019-56133-3

Abstract

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.

Highlights

Aging is the major risk factor driving age-dependent memory impairment (AMI) even in the absence of neurodegenerative diseases, representing one of the top health burden of the 21st century[1]
Based on previous studies demonstrating that spermidine supplementation stimulates autophagy[7,20], we set up several independent cohorts of aged mice undergoing a six-months long spermidine treatment in their drinking water, starting at 18 months of age
We focused on hippocampal granule cells that form mossy fiber (MF) synapses onto CA3 pyramidal neurons

Summary

Introduction

Aging is the major risk factor driving age-dependent memory impairment (AMI) even in the absence of neurodegenerative diseases, representing one of the top health burden of the 21st century[1]. First analysis in aging mice has shown that spermidine feeding prolongs life span and exerts cardioprotective effects[7,13] by Molecular Pharmacology and Cell Biology, Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany. We show that both types of hippocampal synapses suffer from an aging-induced decrease in synaptic vesicle (SV) density and mitochondria abundance. Dietary spermidine supplementation protected from age-related synaptic alterations and partially restored defective LTP selectively at hippocampal mossy fiber (MF)-CA3 but not CA3-CA1 synapses while preventing the aging-induced loss of neuronal mitochondria at both types of synapses. Our results unravel synapse-specific beneficial effects of spermidine at hippocampal synapses characterized by differential synaptic plasticity, thereby providing information for the future development of potential therapies against AMI

Methods

Results

Conclusion