title: Regulation of presynaptic neurotransmission by macroautophagy.
abstract: mTOR is a regulator of cell growth and survival, protein synthesis-dependent synaptic plasticity, and autophagic degradation of cellular components. When triggered by mTOR inactivation, macroautophagy degrades long-lived proteins and organelles via sequestration into autophagic vacuoles. mTOR further regulates synaptic plasticity, and neurodegeneration occurs when macroautophagy is deficient. It is nevertheless unknown whether macroautophagy modulates presynaptic function. We find that the mTOR inhibitor rapamycin induces formation of autophagic vacuoles in prejunctional dopaminergic axons with associated decreased axonal profile volumes, synaptic vesicle numbers, and evoked dopamine release. Evoked dopamine secretion was enhanced and recovery was accelerated in transgenic mice in which macroautophagy deficiency was restricted to dopaminergic neurons; rapamycin failed to decrease evoked dopamine release in the striatum of these mice. Macroautophagy that follows mTOR inhibition in presynaptic terminals, therefore, rapidly alters presynaptic structure and neurotransmission.
authors.affiliation: Department of Neuroscience, Columbia University Medical Campus, New York, NY 10013, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hernandez
authors.forename: Ciara A
authors.initials: CA
authors.lastname: Torres
authors.forename: Wanda
authors.initials: W
authors.lastname: Setlik
authors.forename: Carolina
authors.initials: C
authors.lastname: Cebrián
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.forename: Guomei
authors.initials: G
authors.lastname: Tang
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Cheng
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Olga
authors.initials: O
authors.lastname: Yarygina
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
authors.forename: Michael
authors.initials: M
authors.lastname: Gershon
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000071193:Autophagy-Related Protein 7; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004563:Electrochemistry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D050483:Dopamine Plasma Membrane Transport Proteins; D007166:Immunosuppressive Agents; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C011799:5-hydroxy-2-N,N-dipropylaminotetralin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D014446:Tyrosine 3-Monooxygenase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7; D004298:Dopamine; D020123:Sirolimus