title: Retrograde changes in presynaptic function driven by dendritic mTORC1.
abstract: Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatic trans-synaptic control of presynaptic function. Our findings thus reveal that mTORC1-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORC1 signaling.
authors.affiliation: Neuroscience Graduate Program, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Fredrick E
authors.initials: FE
authors.lastname: Henry
authors.forename: Amber J
authors.initials: AJ
authors.lastname: McCartney
authors.forename: Ryan
authors.initials: R
authors.lastname: Neely
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Perez
authors.forename: Cynthia J L
authors.initials: CJ
authors.lastname: Carruthers
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stuenkel
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases