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

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.

Cortical control of striatal fast-spiking interneuron synchrony.

Inhibitory fast-spiking interneurons in the dorsal striatum regulate actions and action strategies, including habits. Fast-spiking interneurons are widely believed to synchronize their firing due to the electrical synapses formed between these neurons. However, neuronal modelling data suggest convergent cortical input may also drive synchrony in fast-spiking interneuron networks. To better understand how fast-spiking interneuron synchrony arises, we performed dual whole-cell patch clamp electrophysiology experiments to inform a simple Bayesian network modelling cortico-fast-spiking interneuron circuitry. Dual whole-cell patch clamp electrophysiology revealed that while responsivity to corticostriatal input activation was high in fast-spiking interneurons, few of these neurons exhibited electrical coupling in adult mice. In simulations of a cortico-fast-spiking interneuron network informed by these data, the degree of glutamatergic cortical convergence onto fast-spiking interneurons significantly increased fast-spiking interneuron synchronization while manipulations of electrical coupling between these neurons exerted relatively little impact. These results suggest that the primary source of functional coordination of fast-spiking interneuron activity in adulthood arises from convergent corticostriatal input activation. KEY POINTS: Electrical synapses between striatal fast-spiking interneurons in adult mice occur in ∼8% of assayed pairs. Coincident, convergent cortical input onto fast-spiking interneurons significantly contributes to fast-spiking interneuron synchrony. Electrical synapses between fast-spiking interneurons provide only minor enhancement of fast-spiking interneuron synchrony. These results suggest a mechanism by which adult mouse fast-spiking interneurons of the striatum synchronize in the face of declining expression of the electrical synapse-forming connexin-36 protein.