Neuronal mTOR Outposts: Implications for Translation, Signaling, and Plasticity

Abstract

The kinase mTOR is a signaling hub for pathways that regulate cellular growth. In neurons, the subcellular localization of mTOR takes on increased significance. Here, we review findings on the localization of mTOR in axons and offer a perspective on how these may impact our understanding of nervous system development, function, and disease. We propose a model where mTOR accumulates in local foci we term mTOR outposts, which can be found in processes distant from a neuron’s cell body. In this model, pathways that funnel through mTOR are gated by local outposts to spatially select and amplify local signaling. The presence or absence of mTOR outposts in a segment of axon or dendrite may determine whether regional mTOR-dependent signals, such as nutrient and growth factor signaling, register toward neuron-wide responses. In this perspective, we present the emerging evidence for mTOR outposts in neurons, their putative roles as spatial gatekeepers of signaling inputs, and the implications of the mTOR outpost model for neuronal protein synthesis, signal transduction, and synaptic plasticity.

The brain's dark transcriptome: Sequencing RNA in distal compartments of neurons and glia

“…The copy number for any given RNA molecule in the dendritic subtranscriptome is far less than the number of synapses per neuron, indicating that there is no standard subtranscriptome module present at each synaptic site. These spatial transcriptomic data rather point to more heterogeneous clusters in the dendritic subtranscriptome with sparse foci along different dendritic segments, with interesting implications for hypothesis involving synapse-specific local translation in long-term plasticity [ 52 , 53 ].…”

“…Together with the evidence that presynaptic subtranscriptomes exist and are translated in the adult brain, these data point to an interesting layer of diversity at synapses: some will have and some will not have presynaptic subtranscriptomes. Given the robust evidence that plasticity and learning require local translation [ 25 , 65 ], the presence of a translation-competent subtranscriptome at select axon terminals may function as an intersectional filter for which synapses can—and which synapses cannot—undergo translation-dependent long-term plasticity [ 53 ].…”

“…An alternative model is that growing processes, such as growth cones, supply a significant amount of ribosomal protein for the rest of the cell. We have suggested that a potential benefit for such circuitous trafficking of RNA and protein may be regulation of cell-wide ribosomal content by the local conditions at sites of most intense growth [ 60 ], proposed in neurons as the mTOR outpost model [ 53 ]. It is supported by the finding that transcripts for most—if not all—ribosomal proteins are enriched in leading processes, not just those available for local replacement on the surface of ribosomes [ 6 , 25 , 76 ].…”

Control of circadian rhythm on cortical excitability and synaptic plasticity

“…In neurons, mTOR is crucial not only for cell housekeeping but also for local protein synthesis in dendrites, in dendritic spines and in axons ( Altas et al, 2022 ). Indeed, activity dependent local activation of mTOR is required for consolidation of long-term memory ( Nguyen, 2002 ; Cammalleri et al, 2003 ; Kelleher et al, 2004 ; Tsokas et al, 2007 ; Buffington et al, 2014 ).…”