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Traditional linear models depict mTOR signaling as a sequential phosphorylation cascade, but accumulating evidence supports a model that includes signaling through dynamic protein\u2013protein interaction networks. To examine how neuronal mTOR signaling networks discriminate between distinct stimuli, we quantified phosphorylation events and protein co\u2010association networks in primary mouse cortical neurons. Unexpectedly, neuronal mTOR activation by IGF or glutamate triggered dissociation\u2014rather than the anticipated assembly\u2014of protein complexes involving mTOR complex 1 (TORC1), mTOR complex 2 (TORC2), and translational machinery, distinguishing neurons from proliferative cells. Applying in\u00a0vitro homeostatic scaling paradigms revealed distinct combinatorial encoding of synaptic scaling direction: both up\u2010 and down\u2010scaling induced dissociation of translational complexes, but downscaling uniquely included dissociation of upstream pathway regulators. Cortical neurons from Shank3B knockout mice, modeling autism\u2010associated Phelan\u2010McDermid Syndrome, displayed baseline hyperactivation of the mTOR network, which reduced the dynamic range of protein interaction network responses to homeostatic synaptic scaling and pharmacological mTOR inhibition. These findings reveal that neuronal mTOR signaling employs stimulus\u2010specific combinations of dissociative protein interaction modules to encode opposing forms of synaptic plasticity.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70353-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70353","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T13:23:06Z","timestamp":1768396986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dissociation of the\n                    <scp>mTOR<\/scp>\n                    Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation"],"prefix":"10.1111","volume":"170","author":[{"given":"Devin T.","family":"Wehle","sequence":"first","affiliation":[{"name":"Graduate Program in Neuroscience University of Washington  Seattle Washington USA"},{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Graduate Program in Neuroscience University of Washington  Seattle Washington USA"},{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Stamenkovic","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breann","family":"Kniffen","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia M.","family":"Harsh","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4180-573X","authenticated-orcid":false,"given":"Stephen E. 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