Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits
- 1Icahn School of Medicine at Mount Sinai
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.
MethodsTranslational 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.
ResultsWe 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.
ConclusionsThese 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.
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BibTeX
@misc{wengler2026convergent,
title = {{Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits}},
author = {K. Wengler and J. P. Hamm and Y. Shymkiv and K. D. Miller and R. Yuste and G. Horga},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.26363726},
url = {https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits
AU - K. Wengler
AU - J. P. Hamm
AU - Y. Shymkiv
AU - K. D. Miller
AU - R. Yuste
AU - G. Horga
PY - 2026
DA - 2026/09/22
PB - medRxiv
DO - 10.64898/2026.09.22.26363726
UR - https://www.medrxiv.org/content/10.64898/2026.09.22.26363726v1
AB - 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. MethodsTranslational 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. ResultsWe 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. ConclusionsThese 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.
ER -