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

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.

Cellular Senescence in Brain Aging

“…In contrast, CA3 neurons are characterized by an age-related increase in intrinsic excitability and in vivo firing rate. In line with findings for CA1, in CA3 pyramidal neurons no upregulation of L-type Ca 2+ channels has been reported (Maglione et al, 2019) what corroborates with lack of increase in AHP. Increased frequency of action potentials in CA3 pyramidal FIGURE 2 | Age-associated changes in synaptic plasticity at hippocampal and cortical neurons.…”

“…Additionally aged-dependent increase of damaged lysosomes was found leading to autophagy inhibition at the degradation stage (Gomez-Sintes et al, 2016 ; Stoka et al, 2016 ). The turnover of presynaptic proteins, taking place in so called active zones (specific presynaptic structures specialized in neurotransmitter release), was shown to be altered with aging, causing upscaling of the active zone size and abnormal release of synaptic vesicles (Maglione et al, 2019 ). At some point, synapses may reach their upper limit of plasticity potential and lose ability to change, which may translate into learning deficits (Bhukel et al, 2017 ).…”

“…Its beneficial action on the cognitive performance may be associated with promotion of autophagy. It has been shown that simply feeding aged mice with spermidine partially reversed age-related deficits in LTP at mossy fiber-CA3 synapses in the hippocampus (Maglione et al, 2019 ). In line with those results, other modulators of autophagy alleviate age-related cognitive deficits in rodents (Glatigny et al, 2019 ).…”

The quest to slow ageing through drug discovery

“…Because spermidine can reverse the reduction of polyamine synthesis and autophagy observed in aged and osteoarthritic cartilage, it is alaos a promising candidate for prevention of osteoarthritis 218 ,. Finally, spermidine can also improve stem cell function in muscle of old mice 219 , and is neuroprotective in Drosophila 220 and mice 221,222 .…”

Neuronal Mitophagy: Friend or Foe?

“…Spermidine, a natural occurring compound, is shown to induce autophagy and mitophagy promoting cytoprotection, stress resistance and longevity in yeast cells, nematodes, flies, and mice (Eisenberg et al, 2009 , 2016 ; Madeo et al, 2018 ). Furthermore, spermidine-rich feeding reverses the age-induced decline of polyamines in brain tissue and subsequently improves synaptic impairment and memory loss in an autophagy-dependent manner (Gupta et al, 2013 , 2016 ; Maglione et al, 2019 ). A randomized clinical trial was recently conducted to evaluate the impact of spermidine supplementation on memory performance in humans (Wirth et al, 2018 ).…”