Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Signaling

Background:

• The mechanistic target of Rapamycin (mTOR) pathway is crucial for neuronal function and synaptic plasticity.
• Dysregulation of mTOR signaling is linked to neurological and psychiatric disorders.
• Emerging evidence suggests mTOR functions within dynamic protein-protein interaction networks, not just linear cascades.

Purpose of the Study:

• To investigate how neuronal mTOR signaling networks differentiate between stimuli.
• To explore the role of protein-protein interactions in mTOR-mediated synaptic plasticity.
• To examine mTOR network dynamics in a mouse model of autism spectrum disorder.

Main Methods:

• Quantification of phosphorylation events and protein co-association networks in primary mouse cortical neurons.
• Application of in vitro homeostatic synaptic scaling paradigms.
• Analysis of cortical neurons from Shank3B knockout mice.

Main Results:

• Neuronal mTOR activation by IGF or glutamate induced protein complex dissociation, not assembly, involving TORC1, TORC2, and translational machinery.
• Both synaptic up-scaling and down-scaling involved translational complex dissociation, with down-scaling uniquely dissociating upstream regulators.
• Shank3B knockout neurons exhibited baseline mTOR network hyperactivation, reducing dynamic response ranges.

Conclusions:

• Neuronal mTOR signaling utilizes stimulus-specific dissociative protein interaction modules to encode synaptic plasticity.
• Dissociative mechanisms distinguish neuronal mTOR signaling from that in proliferative cells.
• Impaired mTOR network dynamics in Shank3B knockout models contribute to neurological deficits.