{
  "abstract": "ObjectiveNMDA-receptor hypofunction has been implicated as a core pathophysiological mechanism in schizophrenia, but conflicting evidence exists regarding the locus of the hypofunction--i.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\nMethodsTranslational imaging measures--intrinsic neural timescales (INT) and spontaneous co-activation pattern similarity--were investigated in three schizophrenia-relevant mouse models (chronic ketamine administration, n=6; Df(16)A+/-, n=7; and SETD1A+/-, 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\nResultsWe 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. In silico 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\nConclusionsThese 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.",
  "abstract_shown": true,
  "affiliations": [
    "Icahn School of Medicine at Mount Sinai"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "K. Wengler"
    },
    {
      "name": "J. P. Hamm"
    },
    {
      "name": "Y. Shymkiv"
    },
    {
      "name": "K. D. Miller"
    },
    {
      "name": "R. Yuste"
    },
    {
      "name": "G. Horga"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f2y42bwmc4h4g.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.22.26363726",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1.full",
  "id": "f2y42bwmc4h4g",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "psychiatry and clinical psychology"
    ],
    [
      "openalex",
      "2738|Schizophrenia research and treatment"
    ]
  ],
  "openalex": "W7214224473",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/f2y42bwmc4h4g.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:19Z",
      "native_id": "10.64898/2026.09.22.26363726",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:psychiatry and clinical psychology",
      "subfield": "psychiatry"
    }
  ],
  "title": "Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits",
  "title_text": "Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:19Z",
  "url": "https://research.draconitic.com/paper/f2y42bwmc4h4g",
  "venue": "medRxiv",
  "versions": []
}