Transcriptomic analysis reveals pathway-specific targets for hyperlocomotion and social withdrawal in mouse models of...

Schizophreniais a severe mental disorder with complex behavioral pathology and complexgenetic risk.Here, we performed an integrated transcriptomic analysis of the prefrontal cortexin two distinct male C57BL/6J mouse modelsof schizophrenia,the neurodevelopmental methylazoxymethanol acetate (MAM) model (n = 7) and the acute non-competitive N-methyl-D-aspartatereceptor (NMDAR) antagonist MK-801model (n = 6, control n  = 8),compared to that of human patients. Differentially expressed genes in the MK-801 model displayed a modest correlation with that of schizophrenia patients (r = 0.40, p = 2.7 × 10^-6), higher than the MAM model (r = 0.15, p = 0.23), underscoring NMDAR antagonism's relevance to the core pathology of the disorder. Using weighted gene co-expression network analysis, we identified 28co-expression modules across the mouse models, with 11modules significantly associated with individual schizophrenia-related behavioral endophenotypes.Notably, the brown module (linked to hyperlocomotion, r = 0.55, p = 0.01) and the darkgrey module (associated with social withdrawal, r = -0.71, p = 3 × 10^-4)were enriched in Wnt and PI3K/Akt signaling pathways, respectively.Pharmacological inhibition of these two pathways specifically rectified corresponding behavioral anomalies in the MK-801 model, highlighting the critical role of altered Wnt and PI3K/Akt signaling in these behavioral domains of schizophrenia-related behaviors and proposing new avenues for therapeutic intervention.