Article

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: 6.75). 11/2012; 32(48):17128-42. DOI: 10.1523/JNEUROSCI.2149-12.2012
Source: PubMed

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.

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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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    eLife Sciences 10/2014; 3. DOI:10.7554/eLife.03581 · 8.52 Impact Factor
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    • "NBQX-or CNQX-mediated blockade of AMPA receptors in the absence of TTX induces two main homeostatic responses: (1) incorporation of new, GluA2-lacking AMPA receptors postsynaptically; and (2) a retrograde signaling process that results in increased presynaptic release properties, such as spontaneous miniature frequency (Thiagarajan et al., 2005; Gong et al., 2007). Similar to the Drosophila system, postsynaptic mammalian Target of Rapamycin Complex1 (mTORC1) drives this retrograde signaling process—albeit through release of Brain-Derived Neurotrophic Factor (BDNF), which is not found in Drosophila (Henry et al., 2012). Also resonant with the Drosophila NMJ, coincident application of a cocktail of N-and P/Q-type calcium channel blockers ω-conotoxin GVIA and ω-agatoxin IVA (CTx/ATx cocktail) completely abolishes the enhanced presynaptic activity induced by 3 h of CNQX exposure (Jakawich et al., 2010). "
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    • "Using rodent hippocampal neurons in culture , researchers have found that disruption of NMDA receptor mediated miniature postsynaptic currents leads to a rapid increase in postsynaptic protein synthesis and a compensatory increase in postsynaptic glutamate receptor expression (Sutton et al., 2006). Further, alterations in synaptic protein synthesis via eIF4E and mTOR were found to be rapidly induced (within 1–2 h) following acute pharmacological blockade of AMPA receptor function using CNQX (Jakawich et al., 2010; Henry et al., 2012). Interestingly, one substrate of this postsynaptic signaling system is BDNF, which is synthesized and released postsynaptically where it activates presynaptic TrkA receptors and enhances presynaptic function (Jakawich et al., 2010). "
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