Maternal obesity and developmental programming of neuropsychiatric disorders: an inflammatory hypothesis

Maternal obesity is associated with the development of a variety of neuropsychiatric disorders; however, the mechanisms behind this association are not fully understood. Comparison between maternal immune activation and maternal obesity reveals similarities in associated impairments and maternal cytokine profile. Here, we present a summary of recent evidence describing how inflammatory processes contribute towards the development of neuropsychiatric disorders in the offspring of obese mothers. This includes discussion on how maternal cytokine levels, fatty acids and placental inflammation may interact with foetal neurodevelopment through changes to microglial behaviour and epigenetic modification. We also propose an exosome-mediated mechanism for the disruption of brain development under maternal obesity and discuss potential intervention strategies

Cellular and behavioral characterization of Pcdh19 mutant mice: subtle molecular changes, increased exploratory behavior and an impact of social environment

Mutations in the X-linked cell adhesion protein PCDH19 lead to seizures, cognitive impairment, and other behavioral comorbidities when present in a mosaic pattern. Neither the molecular mechanisms underpinning this disorder nor the function of PCDH19 itself are well understood. By combining RNA in situ hybridization with immunohistochemistry and analyzing single-cell RNA sequencing datasets, we reveal Pcdh19 expression in cortical interneurons and provide a first account of the subtypes of neurons expressing Pcdh19/PCDH19, both in the mouse and the human cortex. Our quantitative analysis of the Pcdh19 mutant mouse exposes subtle changes in cortical layer composition, with no major alterations of the main axonal tracts. In addition, Pcdh19 mutant animals, particularly females, display preweaning behavioral changes, including reduced anxiety and increased exploratory behavior. Importantly, our experiments also reveal an effect of the social environment on the behavior of wild-type littermates of Pcdh19 mutant mice, which show alterations when compared with wild-type animals not housed with mutants

Contribution de l'interaction croisée Sema 3A/L1CAM dans la régénération axonale après une lésion médullaire

La régénération axonale suite à des lésions du SNC est limitée par des facteurs intrinsèques et extrinsèques aux neurones adultes. Mon projet vise à déterminer, s il est possible, en transformant le signal répulsif de Sema3A en attraction, d améliorer la régénération des axones dans un modèle murin de lésion médullaire. Afin de tester cette hypothèse, j ai utilisé un peptide mimétique de L1CAM capable de bloquer l inhibition de pousse neuritique liée à Sema3A. Parce que l activité du peptide dépend étroitement de la coexpression de L1 et Nrp1 sur les axones, je me suis intéressé à leur distribution dans la moelle épinière adulte. L administration du peptide in vivo n a de façon surprenante aucun effet sur la récupération de la fonction motrice ou sur la régénération axonale. Je me suis ensuite intéressé au rôle que pouvait avoir l environnement sur l activité du peptide. Un modèle de culture sur cryosection m a permis de montrer que l effet du peptide était perdu dans un contexte adulte. De façon intéressante, l effet de répulsion lié à de la Sema3A exogène est également perdu dans ce contexte. Ces résultats indiquent que la modulation du signal Sema3A par le peptide mimétique de L1CAM n est pas sufffisante pour améliorer la régénération axonale et la récupération fonctionnelle suite à une lésion de moelle épinière et suggèrent que Sema3A n est pas directement responsable de l absence de régénération axonale.Lack of axonal regeneration after injury of the adult CNS is attributable to specific features of adult environment and to a reduction in the growth ability of adult axons. We examined whether Sema3A that is upregulated at the site of spinal cord injury exerts a direct effect on axons.To test this hypothesis, we made use of a L1 mimetic able to block growth cone collapse and neurite length reduction that are mediated by Sema3A. Because activity of the peptide relies on the presence of L1 and Nrp1 on axons, we checked for expression of these in the adult spinal cord and show that L1 and Nrp1 colocalize on a subset of axons in the dorsolateral funiculus.Strikingly, delivery of L1 mimetic peptide to mice whose spinal cord was injured did not reveal any improvement of motor recovery or of axonal regeneration. To understand this failure, I developed an assay in which embryonic neurons were grown on sections of adult naïve or injured spinal cord. Injured spinal cord sections reduced neurite length compared to naïve sections, however addition of L1 mimetic peptide did not block this effect, confirming our in vivo results. Strikingly, addition of recombinant Sema3A in this model did not reduce neurite length indicating that adult spinal cord environment is likely to prevent Sema3A signaling.Together, our results show that modulation of Sema3A signal by the L1 mimetic peptide does not promote axon regeneration or motor recovery and suggest that Sema3A does not directly prevent axonal regrowth after spinal cord injury.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

During the development of the cerebral cortex, Cajal-Retzius (CR) cells settle in the preplate and coordinate the precise growth of the neocortex. Indeed, CR cells migrate tangentially from specific proliferative regions of the telencephalon (for example, the cortical hem (CH)) to populate the entire cortical surface. This is a very finely tuned process regulated by an emerging number of factors that has been sequentially revealed in recent years. However, the putative participation of one of the major families of axon guidance molecules in this process, the Semaphorins, was not explored. Here we show that Semaphorin-3E (Sema3E) is a natural negative regulator of the migration of PlexinD1-positive CR cells originating in the CH. Our results also indicate that Sema3E/PlexinD1 signalling controls the motogenic potential of CR cells in vitro and in vivo. Indeed, absence of Sema3E/PlexinD1 signalling increased the migratory properties of CR cells. This modulation implies negative effects on CXCL12/CXCR4 signalling and increased ADF/Cofilin activity

Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits

International audienceLocal endocytic events involving receptors for axon guidance cues play a central role in controlling growth cone behaviour. Yet, little is known about the fate of internalized receptors, and whether the sorting events directing them to distinct endosomal pathways control guidance decisions. Here, we show that the receptor Plexin-D1 contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. This sorting process promotes colocalization of Plexin-D1 with vesicular pools of active R-ras, leading to its inactivation. In the absence of interaction with GIPC1, missorting of Plexin-D1 results in loss of signalling activity. Consequently, Gipc1 mutant mice show specific defects in axonal projections, as well as vascular structures, that rely on Plexin-D1 signalling for their development. Thus, intracellular sorting steps that occur after receptor internalization by endocytosis provide a critical level of control of cellular responses to guidance signals

Impact of insulin on primary arcuate neurons culture is dependent on early-postnatal nutritional status and neuronal subpopulation

<div><p>Nutrition plays a critical role in programming and shaping linear growth during early postnatal life through direct action on the development of the neuroendocrine somatotropic (GH/IGF-1) axis. IGF-1 is a key factor in modulating the programming of linear growth during this period. Notably, IGF-1 preferentially stimulates axonal growth of GHRH neurons in the arcuate nucleus of the hypothalamus (Arc), which is crucial for the proliferation of somatotroph progenitors in the pituitary, thus influencing later GH secretory capacity. However, other nutrition-related hormones may also be involved. Among them, insulin shares several structural and functional similarities with IGF-1, as well as downstream signaling effectors. We investigated the role of insulin in the control of Arc axonal growth using an <i>in vitro</i> model of arcuate explants culture and a cell-type specific approach (GHRH-eGFP mice) under both physiological conditions (normally fed pups) and those of dietary restriction (underfed pups). Our data suggest that insulin failed to directly control axonal growth of Arc neurons or influence specific IGF-1-mediated effects on GHRH neurons. Insulin may act on neuronal welfare, which appears to be dependent on neuronal sub-populations and is influenced by the nutritional status of pups in which Arc neurons develop.</p></div

Correction: IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice.

[This corrects the article DOI: 10.1371/journal.pone.0170083.]