Altered molecular composition of a specific subset of prefrontal cortical excitatory synapses in schizophrenia

• Published in: The Journal of neuroscience p. e0645252025
• Main Authors: Lorincz, Andrea, Ashaber, Maria, Nusser, Zoltan
• Format: Journal Article
• Language: English
• Published: United States 19.08.2025
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.0645-25.2025

Abnormal excitatory synaptic transmission in the human prefrontal cortex has been implicated in the pathophysiology of schizophrenia based primarily on genetic evidence. However, changes in synaptic function cannot be predicted from altered gene expressions, but determining the amount, density and subsynaptic distribution of synaptic proteins is the only reliable indirect readout of function. Detecting proteins in individual synapses of human postmortem tissues has been severely constrained by technical limitations. Here we overcome this limitation by optimizing a high-resolution, quantitative localization method to facilitate antigen recognition at excitatory synapses in postmortem brains of both sexes. Using PSD-95 immunoreactivity as molecular marker of excitatory synapses, we demonstrate the lack of significant differences in synapse density and size in upper cortical layers of control and schizophrenia subjects. The synaptic densities of postsynaptic AMPA and NMDA receptor subunits, presynaptic molecules Bassoon and Munc13-1 are also indistinguishable between control and schizophrenia subjects. The number of Munc13-1 nanoclusters, marking presynaptic neurotransmitter release sites, does not differ either. Excitatory synapses on parvalbumin expressing interneurons contain similar AMPA, but significantly lower NMDA receptor densities in schizophrenia compared to control subjects. Our study provides the first comprehensive comparison of key functionally relevant synaptic proteins in individual human excitatory synapses and demonstrates that changes in the molecular composition of only a specific subset of excitatory synapses may contribute to the pathophysiology of schizophrenia. Significance Statement Abnormal excitatory synaptic transmission in the prefrontal cortex has been implicated in the pathophysiology of schizophrenia. Our study provides novel insights into the molecular mechanisms underlying excitatory synaptic dysfunction in schizophrenia. By utilizing a high-resolution localization method with improved antigen recognition, we provide a comprehensive analysis of the density and subsynaptic distribution of key synaptic proteins in human cortical excitatory synapses. While we found no significant difference in overall synaptic densities and molecular compositions of excitatory synapses, our results reveal a reduction in NMDA receptor density in synapses targeting parvalbumin expressing interneurons in schizophrenia subjects. These findings suggest that changes in the molecular composition of only a specific subset of cortical synapses may contribute to the pathophysiology of schizophrenia.