Castro-Guarda, M. | bioRxiv Science

bioRxiv2026

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

neuroscience↗

bioRxiv2024

Multiomics-based assessment of 2D and 3D human iPSC-cardiomyocyte models of insulin resistance demonstrate metabolic and contractile dysfunction that recapitulates diabetic cardiomyopathy.

In type II diabetes (T2DM), the heart is exposed to hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, leading to insulin resistance and metabolic dysfunction, culminating in diabetic cardiomyopathy (DbCM). Human-centric models of DbCM are needed to provide mechanistic insights and therapeutic targets in a translationally relevant setting. We hypothesised that culturing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in an "insulin resistance" (IR) media, and assessing this using a systems biology approach, would offer a comprehensive evaluation of dysregulated pathways, establishing their suitability as a model of DbCM. Culturing hiPSC-CMs in 2D or 3D as engineered heart tissue (EHT) in IR media induced insulin resistance and activated numerous pathways implicated in DbCM, including metabolic remodelling, mitochondrial dysfunction, extracellular matrix remodelling, and endoplasmic reticulum stress. Pathways involved in fatty acid oxidation were upregulated, while those involved in glucose metabolism were downregulated, which was validated using radioisotope flux measurements. Adaptation to hypoxia, a key component of post-ischaemic remodelling, was blunted in the 2D IR hiPSC-CMs. Combining proteomic and transcriptomic analyses in the IR 3D EHT revealed significant enrichment of DbCM pathways, with subnetworks enriched for several metabolic and diabetes-related pathways. Additionally, IR 3D EHT displayed impaired relaxation, mimicking the diastolic dysfunction observed in T2DM patients. In conclusion, culturing hiPSC-CM in 2D or 3D in an IR media activates multiple mechanisms implicated in the development of DbCM, with IR 3D EHT also recapitulating the diastolic dysfunction present in patients with T2DM.

molecular biology↗