title: Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release.
abstract: 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, CB1activation 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.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA. Electronic address: t.younts@ucl.ac.uk.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Younts
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Monday
authors.affiliation: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1051, Hungary; School of Ph.D. Studies, Semmelweis University, Budapest 1085, Hungary.
authors.forename: Barna
authors.initials: B
authors.lastname: Dudok
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Klein
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Bryen A
authors.initials: BA
authors.lastname: Jordan
authors.affiliation: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1051, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Katona
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA. Electronic address: pablo.castillo@einstein.yu.edu.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D048588:Benzoxazines / Q000494:pharmacology; D066146:Cell Body / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D007395:Interneurons / Q000378:metabolism*; D036881:Long-Term Synaptic Depression; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D056004:Molecular Dynamics Simulation; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D061848:Optical Imaging; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism*; D014176:Protein Biosynthesis; D017966:Pyramidal Cells / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D058570:TOR Serine-Threonine Kinases
keywords: CB1 receptor; GABA; LTD; endocannabinoid; inhibition; interneuron; presynaptic; protein translation; superresolution microscopy; synaptic plasticity