Retrograde changes in presynaptic function driven by dendritic mTORC1

J Neurosci. 2012 Nov 28;32(48):17128-42. doi: 10.1523/JNEUROSCI.2149-12.2012.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Dendrites / genetics
  • Dendrites / metabolism*
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Hippocampus / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Miniature Postsynaptic Potentials / physiology
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Neurons / metabolism*
  • Rats
  • Signal Transduction / physiology
  • Synapses / metabolism*
  • Synaptic Transmission / physiology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases