title: Macroautophagy can press a brake on presynaptic neurotransmission.
abstract: The mechanistic target of rapamycin (MTOR) has been implicated in regulating synaptic plasticity and neurodegeneration, but MTOR's role in modulating presynaptic function through autophagy is unexplored. We studied presynaptic function in ventral dopamine neurons, a system from which neurotransmitter release can be measured directly by cyclic voltammetry. We generated mutant mice that were specifically deficient for macroautophagy in dopaminergic neurons by deleting the Atg7 gene in cells that express the dopamine uptake transporter. Dopamine axonal profiles in the mutant dorsal striatum were ~one third larger in the mutant mice, released ~50% more stimulus-evoked dopamine release, and exhibited more rapid presynaptic recovery than controls. Rapamycin reduced dopamine neuron axon profile size by ~30% in control mice, but had no effect on macroautophagy deficient axons. Acute rapamycin decreased dopaminergic synaptic vesicle density by ~25% and inhibited evoked dopamine release by ~25% in control mice, but not in the Atg7 deficient mutants. Thus, both basal and induced macroautophagy can provide a brake on presynaptic activity in vivo, perhaps by regulating the turnover of synaptic vesicles, and further regulates terminal volume and the kinetics of transmitter release.
authors: Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University Medical Center, New York, NY, USA.
authors: Ciara A
authors: CA
authors: Torres
authors: David
authors: D
authors: Sulzer
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; C045073:Cre recombinase; D019426:Integrases; D000071193:Autophagy-Related Protein 7; D004298:Dopamine; D020123:Sirolimus