Retrograde Changes in Presynaptic Function Driven by Dendritic mTORC1

Neuroscience Graduate Program, Molecular and Behavioral Neuroscience Institute, Life Sciences Institute, and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2012; 32(48):17128-42. DOI: 10.1523/JNEUROSCI.2149-12.2012
Source: PubMed


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.

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    • "BDNF signaling and mTOR activation enhance synaptogenesis and promote synapse unsilencing in cortex (Itami et al., 2003; Luikart and Parada, 2006; Hoeffer and Klann, 2010; Shen and Cowan, 2010). In addition, BDNF can enhance pre-synaptic function (Henry et al., 2012). Our biochemical data show mTOR is localized close to synapses, as evident by its presence in our synaptoneurosome preparations. "
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