Regulation of presynaptic neurotransmission by macroautophagy

Neuron. 2012 Apr 26;74(2):277-84. doi: 10.1016/j.neuron.2012.02.020.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / analogs & derivatives
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Analysis of Variance
  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics*
  • Autophagy-Related Protein 7
  • Behavior, Animal / drug effects
  • Brain / cytology*
  • Brain / metabolism
  • Corpus Striatum / drug effects
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Electrochemistry
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Genotype
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / ultrastructure
  • RNA, Messenger / genetics
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Atg7 protein, mouse
  • Dopamine Plasma Membrane Transport Proteins
  • Immunosuppressive Agents
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • RNA, Messenger
  • 5-hydroxy-2-N,N-dipropylaminotetralin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Tyrosine 3-Monooxygenase
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Autophagy-Related Protein 7
  • Dopamine
  • Sirolimus