Reelin Secreted by GABAergic Neurons Regulates Glutamate Receptor Homeostasis

BACKGROUND: Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons. CONCLUSIONS/SIGNIFICANCE: Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia

Un exemple d’interactions entre le système nerveux central et le système immunitaire au travers du métabolisme du tryptophane

National audienc

Role of the indoleamine 2,3 dioxygenase (IDO), a tryptophan-catabolizing enzyme, in the behavioral and mood alterations induced by cytokines

International audienc

Influence of the course of brain inflammation on the endogenous IL-1 beta/IL-1Ra balance in the model of brain delayed-type hypersensitivity response to bacillus Calmette-Guerin in Lewis rats

Interleukin-1? (IL-1?) is a key player in the pathogenesis of acute and chronic inflammatory diseases at the periphery and in the brain. Its action is regulated by interleukin-1 receptor antagonist (IL-1Ra), the specific endogenous antagonist of IL-1 receptors. The ratio between local concentrations of IL-1Ra and IL-1? is known to influence the initiation and progression of many inflammatory and autoimmune diseases at the periphery. In order to determine whether this is also the case in the brain, brain and plasma concentrations of IL-1? and IL-1Ra were measured by ELISA in a model of chronic brain inflammation in Lewis rats, the hippocampal delayed-type hypersensitivity (DTH) response to bacillus Calmette–Guérin (BCG). Brain IL-1? increased rapidly after intracerebral (i.c.) injection of BCG and came back to baseline concentrations 1 week later, whereas IL-1Ra increased gradually over time and remained elevated during the last 2 weeks post-BCG intracerebral injection. Following peripheral BCG challenge, brain IL-1? increased at the site of the brain BCG and peaked 12 days later before decreasing on day 16 post-challenge. Brain IL-1Ra remained elevated during the first days post-challenge and then decreased from the 12th day post-challenge. The same temporal variations were observed in the plasma concentrations of IL-1? and IL-1Ra. The increase in the IL-1?/IL-1Ra ratio that was apparent from day 3 to day 12 post-challenge might be correlated with the invasion of peripheral inflammatory cells at the site of intracerebral injection. Besides showing that the course of inflammation alters the brain IL-1?/IL-1Ra ratio, these findings point to the importance of monitoring plasma IL-1?/IL-1Ra ratio to predict the course of brain inflammation

Bacille Calmette-Guérin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice

International audienc

The ERANOS Code and data system for fast reactor neutronic analyses

International audienceThe main modelling options of ERANOS 2.0, the latest version of the ERANOS fast reactor analysis code and data system, are described. These include the ECCO cell and lattice code (Collision Probability Method in many groups using the subgroup method), the BISTRO 2-D S n transport code, the TGV/VARIANT 3-D Nodal Variational Transport code, and a special procedure for creating equivalent homogeneous cross sections for control rods. The recommended "reference" core calculation route is presented. A summary of the ERANOS extensive validation is provided. It is concluded that ERANOS 2.0 can predict the main characteristics of conventional as well as advanced liquid-metal-cooled fast reactors with an excellent accuracy, and that it can also be used for modelling advanced fast reactor cores, source-driven sub-critical media and gas-cooled fast reactors

Bimodal control of fear-coping strategies by CB₁ cannabinoid receptors

International audienceTo maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB₁) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB₁ receptors in CB₁⁻/⁻ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB₁ receptors from cortical glutamatergic neurons. CB₁ receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB₁ receptor agonist Δ⁹-tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB₁ receptors in the amygdala of CB₁⁻/⁻ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB₁ receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear