Developmental Bioenergetic Reprogramming and Glycolytic Shift in Schizophrenia Vulnerability

Schizophrenia (SZ) arises from complex gene-environment interactions, yet how early insults shape later circuit vulnerability remains unclear. Here, we investigated whether bioenergetic states represent a convergent disease signature across genetic and environmental risk factors. We analyzed transcriptional profiles across neocortical development in murine models of maternal immune activation (polyIC MIA), and serine racemase deletion (Srr-/-), extending these analyses to juvenile stages in Srr-/- and interneuron-specific NMDA receptor deletion (Nkx2.1:Grin1fl/fl), highlighting cell-type-specific metabolic vulnerability across developmental stages. In MIA, early gestation (E12.5) revealed a transient bioenergetic shift likely driven by microglial and radial glial populations, suggesting metabolic priming rather than canonical inflammatory signaling. By late gestation (E17.5), MIA induced coordinated dysregulation of neuronal glycolytic isoforms alongside mitochondrial and lipid-associated metabolic pathways, suggesting coordinated metabolic remodeling involving lipid-linked processes. In contrast, Srr-/- mice showed minimal glycolytic alterations at E17.5, indicating that isolated genetic perturbation is insufficient to recapitulate this fetal metabolic state. However, at juvenile stages, region-specific bioenergetic adaptations emerged. Srr-/- mice exhibited global cortical increases in glycolytic gene expression, with hippocampal changes potentially enriched in neuronal populations. Conversely, Nkx2.1:Grin1fl/flinterneurons showed increased glycolytic and TCA cycle transcription in the hippocampus but opposing patterns in the medial prefrontal cortex. Together, these findings identify increased glycolytic activity, potentially linked to lactate metabolism, as a partially convergent developmental mechanism bridging prenatal perturbations and later circuit dysfunction in SZ, and suggest that downstream glycolysis-linked pathways may contribute to phenotypic heterogeneity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/723970v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1dd1461org.highwire.dtl.DTLVardef@1651b65org.highwire.dtl.DTLVardef@e98bc8org.highwire.dtl.DTLVardef@d813a2_HPS_FORMAT_FIGEXP M_FIG C_FIG