Homeostatic plasticity functions within the nervous system to maintain normal neural functions, such as neurotransmission, within predefined optimal ranges. The defined output of these neuronal processes is referred to as the set point, which is the value that the homeostatic system defends against fluctuations. Currently, it is unknown how stable homeostatic set points are within the nervous system. In the present study we used the CM9 neuromuscular junctions (NMJs) in the adult Drosophila to investigate the stability of the set point of synaptic homeostasis across the lifespan of the fly. At the fly NMJ, it is believed that the depolarization of the muscle by neurotransmitter during an action potential, represented by the EPSP, is a homeostatic set point that is precisely maintained via changes in synaptic vesicle release. We find that the amplitude of the EPSP abruptly increases during middle age and that this enhanced EPSP 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 NMJ, appropriate for a synapse at which the set point has been increased. Our data demonstrate that the amplitude of the EPSP at the Drosophila NMJ increases during aging and that the homeostatic signaling system adjusts its response to accommodate the new set point.

SUMMARY Synaptic activity-induced calcium (Ca 2+ ) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca 2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer’s disease and related tauopathies, on nuclear Ca 2+ . We find that pathogenic tau depletes nuclear Ca 2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila , and that activation of big potassium (BK) channels elevates nuclear Ca 2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca 2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer’s disease.

Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP). A critical target of this regulatory mechanism is Complexin, a synaptic protein known to regulate synaptic vesicle exocytosis. We find that the amounts of Complexin protein observed at the synapse is regulated by insulin and genetic manipulations of Complexin levels support the model that increased synaptic Complexin reduces neurotransmission in response to insulin signaling.DOI: http://dx.doi.org/10.7554/eLife.16807.001

Summary Synaptic dysfunction is considered the primary substrate for the functional declines observed within the nervous system during age-related neurodegenerative disease. Dietary restriction (DR), which extends lifespan in numerous species, has been shown to have beneficial effects on many neurodegenerative disease models. Existing data sets suggest that the effects of DR during disease include the amelioration of synaptic dysfunction but evidence of the beneficial effects of diet on the synapse is lacking. Dynactin mutant flies have significant increases in mortality rates and exhibit progressive loss of motor function. Using a novel fly motor disease model, we demonstrate that mutant flies raised on a low calorie diet have enhanced motor function and improved survival compared to flies on a high calorie diet. Neurodegeneration in this model is characterized by an early impairment of neurotransmission that precedes the deterioration of neuromuscular junction (NMJ) morphology. In mutant flies, low calorie diet increases neurotransmission, but has little effect on morphology, supporting the hypothesis that enhanced neurotransmission contributes to the effects of diet on motor function. Importantly, the effects of diet on the synapse are not due to the reduction of mutant pathologies, but by the increased release of synaptic vesicles during activity. The generality of this effect is demonstrated by the observation that diet can also increase synaptic vesicle release at wild type NMJs. These studies reveal a novel presynaptic mechanism of diet that may contribute to the improved vigor observed in mutant flies raised on low calorie diet.