Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release

PLoS Biol. 2016 Sep 29;14(9):e1002563. doi: 10.1371/journal.pbio.1002563. eCollection 2016 Sep.

Abstract

Memories are assumed to be formed by sets of synapses changing their structural or functional performance. The efficacy of forming new memories declines with advancing age, but the synaptic changes underlying age-induced memory impairment remain poorly understood. Recently, we found spermidine feeding to specifically suppress age-dependent impairments in forming olfactory memories, providing a mean to search for synaptic changes involved in age-dependent memory impairment. Here, we show that a specific synaptic compartment, the presynaptic active zone (AZ), increases the size of its ultrastructural elaboration and releases significantly more synaptic vesicles with advancing age. These age-induced AZ changes, however, were fully suppressed by spermidine feeding. A genetically enforced enlargement of AZ scaffolds (four gene-copies of BRP) impaired memory formation in young animals. Thus, in the Drosophila nervous system, aging AZs seem to steer towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation. Spermidine feeding suppresses age-dependent memory impairment by counteracting these age-dependent changes directly at the synapse.

Grant support

This work was supported by grants from the Bundesministerium für Bildung und Forschung (Smartage, 01GQ1420A) to SJS and CB, the Forschungszentrum für neurodegenerative Erkrankungen to SJS and AE, and the Deutsche Forschungsgemeinschaft to SJS and AB (Exc 257, TP A3 and A6 SFB 958; SFB 740 TP C09). UP and AF were supported by the German Research Foundation (SFB 889/B04) and the German Ministry of Research and Education via the Bernstein Center for Computational Neuroscience Göttingen (grant number 01GQ1005A). FM is grateful to the Austrian Science Fund FWF for grants P23490-B12, P24381, P 27893, I1000 and grant ‘SFB Lipotox’ and to BMWFW and the Karl-Franzens University for grant ‘Unkonventionelle Forschung'. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.