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 (BDNF) 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.

Homeostatic Control of Presynaptic Neurotransmitter Release

“…An intriguing possibility is that the TOR/S6K signaling system represents a metabolic sensor that detects prolonged changes in synaptic transmission. This idea is consistent with experiments implicating a function for TOR-dependent signaling downstream of AMPA receptor blockade in mammalian neurons (54). The potential importance of this signaling system for homeostasis in vivo is emphasized in experiments demonstrating that TOR signaling is essential for balanced network excitation and inhibition in mammals (83).…”

“…The search for molecular mechanisms has been driven, in part, by a candidate-based approach in mammalian cell culture and the Drosophila NMJ, with some notable successes, including the implication of CDK5 (42,44), mTOR (54,55), and microRNA-based signaling (31,33). However, if the ultimate goal is to define the molecular architecture of a homeostatic regulatory system that includes poorly defined parameters such as a set point, error signal, and proportional feedback, then there are no candidates to try.…”

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

“…In addition, mTORC1 likely directly controls BDNF synthesis and release to dendrites (Henry et al, 2012). mTORC1 contributes to the dendritic translation and surface expression of GluR1, GluR2, and perhaps other synaptic proteins (Ran et al, 2013;Wang et al, 2006).…”

A recollection of mTOR signaling in learning and memory

“…This leads to a mTORC1-dependent increase in the synthesis of a retrograde messenger that then acts presynaptically to increase neurotransmitter release, thus restoring basal synaptic strength (Henry et al 2012;Penney et al 2012). In these cases mTORC1 activation appears to be sufficient, as either overexpression of RHEB (the mTORC1-specific activator), or overexpression of a constitutively active downstream target of mTORC1 in Drosophila, induces the increase in presynaptic neurotransmitter release (Henry et al 2012;Penney et al 2012). Thus, a major physiological effect of activating mTORC1 at the postsynaptic density is to increase neurotransmitter release from the presynaptic neurons.…”