Convergent multidimensional neural phenotypes in human patients and schizophrenia-relevant mouse models identify reduced recurrent excitation in cortical circuits

Objective. NMDA-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. Methods. Translational 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. Results. 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. 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. Conclusions. 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.