Impairment of one-carbon metabolism during pregnancy, either due to nutritional deficiencies in B9 or B12 vitamins or caused by specific genetic defects, is often associated with neurological defects, including cognitive dysfunction that persists even after vitamin supplementation. Animal nutritional models do not allow for conclusions regarding the specific brain mechanisms that may be modulated by systemic compensations. Using the Cre-lox system associated to the neuronal promoter Thy1.2, a knock-out model for the methionine synthase specifically in the brain was generated. Our results on the neurobehavioral development of offspring show that the absence of methionine synthase did not lead to growth retardation, despite an effective reduction of both its expression and the methylation status in brain tissues. Behaviors were differently affected according to their functional outcome. Only temporary retardations were recorded in the acquisition of vegetative functions during the suckling period, compared to a dramatic reduction in cognitive performance after weaning. Investigation of the glutamatergic synapses in cognitive areas showed a reduction of AMPA receptors phosphorylation and clustering, indicating an epigenomic effect of the neuronal deficiency of methionine synthase on the reduction of glutamatergic synapses excitability. Altogether, our data indicate that cognitive impairment associated with methionine synthase deficiency may not only result from neurodevelopmental abnormalities, but may also be the consequence of alterations in functional plasticity of the brain.

Introduction: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major clinical challenge, characterized by heterogeneous manifestations and the absence of reliable biomarkers. The mechanisms linking systemic autoimmunity to neuronal injury and neuropsychiatric symptoms remain poorly understood. Methods: Using the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mapping, cortical metabolomics, and behavioral analyses to dissect immune–metabolic–neuronal interactions. Results: Inflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as the central driver. Composite cytokine scores correlated strongly with plasma NfL, establishing an immune–neuronal injury axis. Region-resolved analyses revealed distinct CNS cytokine signatures, including selective hippocampal loss of interleukin-10 and IFNγ-dominated responses in the frontal cortex. Cortical metabolomics demonstrated diversion of tryptophan metabolism away from serotonin toward the kynurenine pathway, with increased quinolinic acid/kynurenic acid (QA/KA) ratio and upregulation of indoleamine 2,3-dioxygenase-1 ( Ido1 ) and kynurenine 3-monooxygenase ( Kmo ). NfL levels were negatively associated with serotonin and positively with 3-hydroxykynurenine and QA/KA, linking axonal damage to an excitotoxic metabolic environment. Importantly, cortical serotonin levels correlated with exploratory behavior, linking serotonergic depletion to anxiety-like phenotypes. Discussion: Together, these results delineate a cascade in which systemic IFNγ is associated with cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood or CSF monitoring of IFNγ, NfL, and kynurenine metabolites could represent a candidate biomarker framework for NPSLE. However, validation in independent patient cohorts will be essential, and therapeutic modulation of IDO1/KMO or serotonergic pathways remains an avenue for future investigation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet its hippocampal molecular underpinnings remain poorly understood. Here, we provide a region-specific transcriptomic map of the hippocampus in MRL/Lpr mice —a validated NPSLE model— compared to MRL ^+/+ controls. Bulk RNA-seq combined with integrative analyses ( e.g. differential expression, GSEA, WGCNA, cell-type deconvolution) uncovered a robust disease-specific signature centered on oligodendrocyte dysfunction and myelination failure. Key myelin-related genes ( Mbp , Plp1 , Mog ) and lineage-defining transcription factors ( Sox10 , Nkx6-2 , Olig2 ) were repressed, while OPC markers remained unchanged, indicating a maturation blockade rather than lineage loss. Gene set enrichment highlighted widespread suppression of oligodendrocyte differentiation, axon ensheathment, and Wnt/retinoic acid signaling, alongside dysregulation of extracellular matrix components critical for axo-glial interactions. Co-expression network analysis revealed a disease-associated module enriched in myelination programs, with hub genes spanning structural, transcriptional, and adhesion-related functions. Deconvolution analysis confirmed a selective reduction of mature oligodendrocytes, contrasting with preserved neuronal populations and absence of classical astroglial or microglial activation signatures. RT-qPCR and Western blot validated the repression of myelination pathways at both mRNA and protein levels. Collectively, these findings challenge the inflammation-centric paradigm of NPSLE, revealing a cell-intrinsic vulnerability of the oligodendrocyte lineage. This conceptual shift — from immune-driven damage to impaired glial development— redefines NPSLE pathogenesis and suggests novel therapeutic avenues targeting oligodendrocyte maturation and remyelination rather than focusing solely on immunosuppression.

Systemic lupus erythematosus (SLE) displays marked clinical and biological heterogeneity that is incompletely captured by group-based analyses. Although the MRL/Lpr mouse is a well-established lupus model, individual-level divergence within this genetically homogeneous strain remains poorly characterized. Here, we describe an MRL/Lpr mouse exhibiting an exceptionally severe systemic phenotype and provide an integrative characterization combining clinical assessment, inflammatory profiling, neuroaxonal injury, and targeted metabolomics. Despite pronounced clinical deterioration, including severe proteinuria, reduced organ weights, and marked neuroaxonal damage, this mouse did not show a globally exacerbated cytokine profile relative to other MRL/Lpr animals. In contrast, plasma neurofilament light chain levels were massively elevated, indicating substantial neuroaxonal injury. Targeted metabolomic analysis revealed a profoundly altered biochemical signature, with coordinated disruptions in nitrogen handling, sulfur amino acid metabolism, and neurometabolic pathways, clearly separating this animal from both control and lupus-prone peers.

Les défauts innés du métabolisme de la vitamine B12 (cobalamine) incluant la pathologie CblG causée par des mutations du gène MTR codant pour l’enzyme méthionine synthase (MS) sont responsables du développement de symptômes persistants aux traitements en particulier des symptômes neurologiques, neurocognitifs et ophtalmologiques. Cependant les mécanismes sous-jacents au développement de ces symptômes restent largement méconnus. L’objectif de ce projet est d’étudier dans un modèle murin conditionnel de déficience en MS, les conséquences de la délétion du gène Mtr dans le cerveau et dans la rétine afin d’apporter une meilleure compréhension des mécanismes à l’origine des troubles neurologiques, neurocognitifs et oculaires retrouvés chez les patients CblG. Nous avons constaté que l'invalidation sélective de Mtr dans le cerveau entraine des altérations métaboliques sévères. Nos résultats ont mis en évidence une dérégulation de la voie de signalisation Wnt/β.caténine impliquant directement la protéine GSK3β et la protéine SIRT1, affectant ainsi la neurogenèse postnatale à travers une dérégulation de la balance de différenciation associée à une altération de la prolifération des cellules souches neurales et progénitrices. Ces défauts de neurogenèse semblent s’accompagner d’anomalies du métabolisme énergétique ainsi que de la biogenèse mitochondriale impliquant la protéine SIRT1 et favorisant ainsi l’activation de la cascade apoptotique intrinsèque dans l’hippocampe des souris déficientes en MS. Ces anomalies de neurogenèse ainsi que les altérations mitochondriales semblent être deux mécanismes majeurs participant au développement des troubles neurologiques. Les protéines GSK3β et SIRT1 semblent être deux cibles thérapeutiques d’intérêts dans l’optique d’un traitement visant à corriger les défauts neurologiques dans la pathologie CblG.Dans la rétine l’invalidation de la MS a entrainé des altérations métaboliques majeures associées à des modifications de la méthylation de l’ADN ainsi qu’à une baisse de l’acuité visuelle chez les souris MS déficientes sans pour autant entrainer d’anomalies visibles du fond d’œil. Les résultats de notre étude ont permis de mettre en évidence une possible implication de gènes du métabolisme des rétinoïdes associée à une baisse spécifique des cellules photoréceptrices de type cône pouvant ainsi participer à la baisse de l’acuité visuelle chez les souris déficientes en MS. Ces travaux préliminaires nécessiteront d’autres investigations, mais apportent cependant pour la première fois l’évidence d’anomalies rétiniennes en condition de déficience en MS.