Mechanisms of age and diet on the potentiation of synaptic vesicle release at the adult Drosophila neuromuscular junction.

摘要

During the aging process there is a steady decline in cognitive abilities, especially in regards to learning and memory. These age related decreases in cognitive performance observed during normal aging also tend to be less severe than those observed in age-associated disorders, such as those seen during the progression of Parkinson's and Alzheimer's disease. It should be noted that age-dependent changes in synaptic strength have previously been observed at both mammalian neuromuscular junctions and central synapses, suggesting that age-dependent potentiation of synaptic vesicle release could be a common effect of age at many synapses. This is a particularly appealing hypothesis given that age associated changes at the level of the synapse lead to an overall loss in muscle strength, therefore setting up the idea that a compensatory homeostatic pathway could be active within these synapses therefore negating any loss in synaptic function with age. At the fly neuromuscular junction, it is believed that the depolarization of the muscle by neurotransmitter during an action potential, represented by the endplate synaptic potential, is a homeostatic set point that is precisely maintained via changes in synaptic vesicle release. We find that the amplitude of the endplate synaptic potential abruptly increases during middle age and that this enhanced endplate synaptic potential is maintained into late life, consistent with an age-dependent change to the homeostatic set point of the synapse during middle age. In support of this, comparison of the homeostatic response at the young versus the old synapse shows that the magnitude of the homeostatic response at the older synapse is significantly larger than the response at the young neuromuscular junction, appropriate for a synapse at which the set point has been increased. Our data demonstrate that the amplitude of the endplate synaptic potential at the Drosophila neuromuscular junction increases during aging and that the homeostatic signaling system adjusts its response to accommodate the new set point.;The age-dependent decline in brain function, largely characterized by reduced short-term and working memory, is a significant detriment to the quality of life for the elderly. The effects of aberrant insulin signalling within the brain has been extensively linked to an increase in the prevalence of cognitive dysfunction and neurodegenerative disease, although the exact cellular mechanisms underlying the effects of insulin on neurotransmission remain unclear. Here we show that insulin signaling negatively regulates neurotransmission in the adult Drosophila motor neuron. We have found that cell autonomous insulin signaling negatively regulates the presynaptic release of neurotransmitter via the activity of the eukaryotic initiation factor 4e binding protein, a negative regulator of protein translation. In support, the effects of insulin are also blocked by the translation inhibitor cycloheximide. In this context, the activity of elongation factor 4e binding protein is regulated transcriptionally, by the Forkhead transcription factor, and not due to its phosphorylation by the mammalian target of rapamycin. The effects of insulin are also blocked by knock-down of Staufen, a Ribonucleic acid binding protein which has been shown to bind both eukaryotic initiation factor 4e binding protein and complexin messenger Ribonucleic acids in motor neurons. Our data supports the model that autonomous insulin signaling regulates the presynaptic release of neurotransmitter via the translation of complexin messenger Ribonucleic acid.