{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:05:59Z","timestamp":1790283959202,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01MH134973"],"award-info":[{"award-number":["R01MH134973"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:p>\n                  <jats:bold>Objective.<\/jats:bold>\n                  NMDA-receptor hypofunction has been implicated as a core pathophysiological mechanism in schizophrenia, but conflicting evidence exists regarding the locus of the hypofunction\u2014i.e. predominantly affecting receptors on pyramidal neurons or interneurons. To investigate the locus of NMDA-receptor hypofunction we integrated imaging data from humans and mice with biophysical model simulations.\n                  <jats:bold>Methods.<\/jats:bold>\n                  Translational imaging measures\u2014intrinsic neural timescales (INT) and spontaneous co-activation pattern similarity\u2014were investigated in three schizophrenia-relevant mouse models (chronic ketamine administration, n=6;\n                  <jats:italic>\n                    Df(16)A\n                    <jats:sup>+\/-<\/jats:sup>\n                  <\/jats:italic>\n                  , n=7; and\n                  <jats:italic>\n                    SETD1A\n                    <jats:sup>+\/-<\/jats:sup>\n                  <\/jats:italic>\n                  , n=9) and matched control mice (n=5; n=7; and n=8, respectively) using two-photon calcium imaging, and individuals with schizophrenia (n=127) and matched non-clinical controls (n=152) using functional MRI. The stabilized supralinear network biophysical model was used to simulate NMDA-receptor hypofunction and its impact on the translational imaging measures.\n                  <jats:bold>Results.<\/jats:bold>\n                  We identified convergent neural phenotypes of shorter intrinsic neural timescales (INT) and reduced spontaneous co-activation pattern similarity in both the schizophrenia-relevant mouse models and the individuals with schizophrenia compared to matched controls.\n                  <jats:italic>In silico<\/jats:italic>\n                  simulations using the stabilized supralinear network biophysical model recapitulated the convergent neural phenotypes through reduced excitatory-to-excitatory connection strength (i.e. NMDA-receptor hypofunction on pyramidal neurons) and predicted that INT and pattern similarity are correlated; this prediction was confirmed in both the mouse and human data.\n                  <jats:bold>Conclusions.<\/jats:bold>\n                  These results identify NMDA-receptor hypofunction on pyramidal neurons as a general and translationally valid mechanism for NMDA-receptor hypofunction in schizophrenia. These convergent translational findings suggest prioritizing the development of treatments for schizophrenia that increase recurrent excitation.\n                <\/jats:p>","DOI":"10.64898\/2026.09.22.26363726","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:55:20Z","timestamp":1790283320000},"source":"Crossref","is-referenced-by-count":0,"title":["Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8153-5183","authenticated-orcid":false,"given":"Kenneth","family":"Wengler","sequence":"first","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-6121","authenticated-orcid":false,"given":"Jordan P","family":"Hamm","sequence":"additional","affiliation":[{"name":"New York University, Nathan Kline Institute for Psychiatric Research;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9086-8273","authenticated-orcid":false,"given":"Yuriy","family":"Shymkiv","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D","family":"Miller","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Yuste","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9049-9786","authenticated-orcid":false,"given":"Guillermo","family":"Horga","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.22.26363726","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:55:20Z","timestamp":1790283320000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.22.26363726"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.09.22.26363726","relation":{},"subject":[],"published":{"date-parts":[[2026,9,24]]},"subtype":"preprint"}}