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Wnt-signaling pathways are dysregulated in female cerebellum following an early methyl donor deficiency in a rat nutritional model

ABSTRACT: Early methyl donor –especially B9 and B12 vitamins- deficiency (MDD) is involved in birth defects and brain development retardation. Molecular mechanisms that take place in response to MDD still remain not well understood. In this study we took advantage of a rat nutritional MDD model and performed a microarray analysis on female cerebellum, in order to identify which genes and molecular pathways are disrupted in response to MDD. We found that cerebellum development is altered, with a decrease of the granular cell layer thickness in cerebellum at P21. Furthermore, we investigated the involvement of Wnt-signaling pathway –a major molecular pathway involved in neuronal development but also later in synaptic assembly and neurotransmission. We found that Wnt canonical and Ca2+ pathways are disrupted following early MDD. Notably, we identified GSK3β as a pivotal player affected by MDD, affecting synaptic assembly and signaling. These results could explain the structural brain defects previously observed in response to early MDD and identify new genes and a new molecular pathway that is affected following nutritional methyl donor deprivation.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE104164 | GEO | 2018/05/11

REPOSITORIES: GEO

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Project description:Background: While stressful events are recognized as an important cause of major depressive disorder (MDD), some individuals exposed to life stressors maintain normal psychological functioning. Although the molecular mechanism(s) underlying this phenomenon remain unclear, abnormal transmission and plasticity of hippocampal synapses may play a key role in the pathoetiology of MDD. Methods: A chronic mild stress (CMS) protocol was applied to separate susceptible and unsusceptible rat subpopulations. Proteomic analysis using an isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry was performed to identify differential proteins in enriched hippocampal synaptic junction preparations. Results: A total of 4318 proteins were quantified, and 89 membrane proteins were present in differential amounts. Of these, SynaptomeDB identified 81 (91%) having a synapse-specific localization. The unbiased profiles identified several candidate proteins within the synaptic junction that may be associated with stress vulnerability or insusceptibility. Subsequent functional categorization revealed that protein systems particularly involved in membrane trafficking at the synaptic active zone exhibited a positive strain as potential molecular adaptations in the unsusceptible rats. Moreover, through STRING and immumoblotting analysis, membrane-associated GTP-bound Rab3a and Munc18-1 appear to co-regulate syntaxin-1/SNAP25/VAMP2 assembly at the hippocampal presynaptic active zone of unsusceptible rats, facilitating SNARE-mediated membrane fusion and neurotransmitter release, and may be part of a stress-protection mechanism in actively maintaining an emotional homeostasis. Conclusions: The present results support the concept that there are a range of potential protein adaptations in the hippocampal synaptic active zone of unsusceptible rats, revealing new investigative targets that may contribute to a better understanding of stress insusceptibility.

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Wnt-signaling pathways are dysregulated in female cerebellum following an early methyl donor deficiency in a rat nutritional model

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