Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release

Neuron. 2016 Oct 19;92(2):479-492. doi: 10.1016/j.neuron.2016.09.040.


Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB1)-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons, but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB1-expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain.

Keywords: CB1 receptor; GABA; LTD; endocannabinoid; inhibition; interneuron; presynaptic; protein translation; superresolution microscopy; synaptic plasticity.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Benzoxazines / pharmacology
  • Cell Body / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Image Processing, Computer-Assisted
  • Imaging, Three-Dimensional
  • Interneurons / metabolism*
  • Long-Term Synaptic Depression*
  • Mice
  • Mice, Inbred C57BL
  • Microscopy
  • Molecular Dynamics Simulation
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neural Inhibition
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism
  • Optical Imaging
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Presynaptic Terminals / metabolism*
  • Protein Biosynthesis*
  • Pyramidal Cells / metabolism
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Ribosomes / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • gamma-Aminobutyric Acid / metabolism*


  • Benzoxazines
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • gamma-Aminobutyric Acid
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • TOR Serine-Threonine Kinases