How Does an Enriched Environment Impact Hippocampus Brain Plasticity?

Brain plasticity is profoundly impacted by one’s living environment. The hippocampus, involved in learning and memory, is highly susceptible to plasticity. Raising rodents in an “enriched environment” (EE) increases learning and memorization aptitudes and decreases the anxiety of the animals. EE consists of a combination of running wheels for voluntary physical exercise, complex inanimate toys, nests, mazes, etc. all of which favor sensory stimulations and social enrichment. EE housing concomitantly increases proliferation and survival of neurons and glia in the dentate gyrus of the hippocampus, induces changes in neuronal morphology, modifies synaptic plasticity, and favors angiogenesis. The mechanisms underlying the effects of EE on plasticity, which have recently been investigated are reviewed here, including the role of glia, the involvement of molecular factors including neurotransmitters (glutamate), neurotrophic factors (BDNF), adipokines (leptin and adiponectin), chemokines, cytokines, and hormones (corticosteroid and thyroid hormones), and at a higher level, the various systems involved (neural networks and hormonal systems). We emphasize recent findings that demonstrate the major role of the immune system in modulating EE-induced changes to hippocampal plasticity. This process involves a variety of immune cells (including macrophages, microglia, natural killer, B-cells, and T-cells), although the mechanisms are yet to be fully elucidated

Prion Protein Is a Key Determinant of Alcohol Sensitivity through the Modulation of N-Methyl-D-Aspartate Receptor (NMDAR) Activity

The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP−/−) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP−/− mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP−/− mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP−/− mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions

Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death

Implication des toxines environnementales, L-BMAA et roténone dans la neurodégénérescence rétinienne

L étiologie des principales pathologies neurodégénératives est source de débats. Leurs fortes incidences au sein de certaines populations ont suggéré l implication de facteurs étiologiques environnementaux. La roténone est une molécule extraite des racines de plantes tropicales. Largement utilisée en laboratoire en tant qu inhibiteur de la chaîne respiratoire mitochondriale, elle est depuis quelques années une des toxines permettant d obtenir des modèles animaux de la maladie de Parkinson. Les parkinsoniens présentant des atteintes visuelles, nous avons étudié la toxicité de la roténone sur la rétine in vivo. Quelle que soit la voie d administration, les enregistrements d électrorétinographie suggèrent que la roténone altère l activité rétinienne chez la souris, en diminuant l amplitude de l onde-b et des potentiels oscillatoires. De façon surprenante, seulement 50% des souris traitées avec la neurotoxine présentent des lésions rétiniennes. Sur des neurones en culture, la neurotoxicité est indépendante de l état d oxydation de la molécule. Le L-BMAA (ß-N-méthylamino-L-alanine) est un acide aminé cyanobactérien produit dans les racines et les graines de Cycas Circinalis. A fortes doses, il provoquerait le complexe pathologique de l île de Guam appelé "Sclérose Latérale Amyotrophique/ Complexe Parkinson-Démence " (SLA/CPD). Les patients atteints par cette maladie présentent pour la grande majorité une rétinopathie spécifique. Nous avons ainsi étudié la toxicité du L-BMAA in vivo sur le modèle rétinien. L analyse des électrorétinogrammes de souris montre que son injection par voie intra-oculaire réduit l amplitude de l onde-b, sans avoir d effet apparent sur celles de l onde-a ou sur les latences de ces deux ondes. Les potentiels oscillatoires présentent également une forte diminution. La mort des cellules rétiniennes est mise en évidence par des analyses histologiques, l activation de la caspase-3, l incorporation d'iodure de propidium et la production de composés oxygénés réactifs. La co-injection d antagonistes spécifiques du récepteur NMDA (MK-801 et Ifenprodil) protège significativement les neurones rétiniens de l apoptose induite par le L-BMAA seul ou additionné de NMDA. Ainsi, d une part nous apportons la preuve que le L-BMAA induit une mort neuronale in vivo, soutenant l hypothèse d un lien de causalité direct entre cette neurotoxine et les dommages neuronaux ; d autre part, nous montrons que la neurotoxicité implique le récepteur NMDA. Le rôle de la Roténone et du L-BMAA dans l étiologie des pathologies neurodégénératives est discuté. Nos travaux montrent que ces deux toxines environnementales sont bel et bien toxiques in vivo sur les neurones rétiniens. Bien que ciblant des populations différentes (respectivement les neurones dopaminergiques et glutamatergiques), leurs effets délétères sont estimés par électrorétinographie, prouvant ainsi l intérêt du modèle rétinien comme méthode d étude in vivo de la toxicité des neurotoxines.NICE-BU Sciences (060882101) / SudocSudocFranceF

Rôle des cellules immunitaires et effets des cannabinoïdes dans la physiopathologie des maladies à prions

L évènement moléculaire clé des maladies à prions est la conversion de la protéine prion cellulaire (PrPc) en une isoforme pathologique et résistance à la protéolyse, nommée (PrPres). La PrPres est responsable de la neuropathogenèse et de la transmissibilité de la maladie. La recherche de molécules capables d inhiber sa formation dans le cerveau est donc une stratégie thérapeutique envisageable. Le cannabidiol, composé non psycho-actif de Cannabis Sativa, inhibe l accumulation de la PrPres aussi bien in vitro qu in vivo et permet de prolonger significativement le temps de survie des souris infectées par les prions. De nombreuses études suggèrent la participation des cellules immunes dans le transport de la PrPres. Grâce à un modèle de déplétion transitoire des cellules dendritiques, nous avons montré que ces cellules étaient impliquées dans le processus de lymphoinvasion après une infection par voie intra-péritonéale mais pas par voie orale. La fonction physiologique de la PrPc est encore mal connue, en particulier dans le système immunitaire. La recherche de partenaires protéiques pourrait permettre de mieux comprendre le rôle de la PrPc. Des traceurs fluorescents composés de PrP recombinante ont été produits et utilisés pour caractériser les sites de liaison de la PrPc dans les différentes populations de splénoctytes murins. La liaison des traceurs sur des lymphocytes B entraîne l'activation de la voie des MAP kinase et l'élévation transitoire de la concentration calcique intracellulaire démontrant que la liaison de la PrPc à ses récepteurs est fonctionnelle. Le rôle physiologique de ces interactions et la nature moléculaire des récepteurs reste à être déterminés.NICE-BU Sciences (060882101) / SudocSudocFranceF

The adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice

International audienceOBJECTIVE:Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances.METHODS:5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure.RESULTS:We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation.CONCLUSION:We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects