Developmental Bioenergetic Reprogramming and Glycolytic Shift in Schizophrenia Vulnerability
Year: 2026
Type: preprint
Abstract: 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:Grin1 fl/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:Grin1 fl/fl interneurons 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
Institutions: Broad Institute, Harvard University, McLean Hospital, Massachusetts General Hospital, Stanley Center for Psychiatric Research, University of Oxford, The Pirbright Institute, Technion – Israel Institute of Technology, University of Szeged, Australian Institute of Tropical Health and Medicine, James Cook University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: McLean Hospital
OpenAlex ID: W7160891899