Récepteur NMDA | EPFL Graph Search

thumb|Représentation schématique d'un récepteur NMDA activé. Le glutamate et la glycine occupent leurs sites de liaison. S'il était occupé, le site allostérique causerait l'inactivation du récepteur. Les récepteurs NMDA requièrent la liaison de deux molécules de glutamate ou d'aspartate et deux de glycine. thumb|Structure de la molécule de NMDA. Les récepteurs NMDA (récepteur au N-méthyl-D-aspartate) sont des récepteurs ionotropes activés dans des conditions physiologiques par le glutamate et la glycine qui sont essentiels à la mémoire et à la plasticité synaptique. Ce sont les seuls récepteurs au glutamate à être spécifiquement activés par l'agoniste pharmacologique N-méthyl-D-aspartate (NMDA). Ils sont perméables aux cations monovalents (sodium, potassium) et au calcium. En raison de la perméabilité au sodium et au potassium, le potentiel de réversion des NMDAR est autour de . L'entrée de calcium dans le neurone via les récepteurs de NMDA serait un mécanisme d'induction de la plasti

Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid

Henry Markram, Tania Rinaldi

Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain unknown. We therefore studied plasticity-related mechanisms in the neocortex of 2-week-old rats prenatally exposed to VPA and tested for changes in glutamate-mediated transmission and plasticity in the neocortex. We found a selective overexpression of NR2A and NR2B subunits of NMDA receptors, as well as the commonly linked kinase calcium/calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes increased plasticity in the neocortex. Enhanced plasticity introduces a surprising perspective to the potential molecular and synaptic mechanisms involved in children prenatally exposed to VPA.

2007

HER receptor dimerization controlled with bivalent ligands

Seymour de Picciotto

In this thesis, I show the ability of engineered bivalent ligands to control HER signaling by taking advantage of the dimerization-dependent mechanism of the four different receptors in the HER (EGFR) family. While monovalent wild-type ligands form HER homoe- and hetero-dimers according to the different members' relative expression levels, I hypothesize that bivalent ligands are able to drive dimerization of specific family members, independently of the cell's HER receptor composition. Using human telomerase reverse transcriptase (hTERT)-immortalized human mesenchymal stem cells (hTMSC), this study first confirms the bioactivity of the bivalent ligands: they exhibit an EC50 one order of magnitude lower than wild-type monomeric ligands and shown an avidity effect as shown from dose-response analysis of the pERK and pY-EGFR nodes. Then, I take advantage of known differences between EGFR hetero- and homodimer to investigate the bivalent ligands' ability to form selective dimers. I demonstrate that bivalent EGF is capable of inducing greater EGFR phosphorylation while preventing HER2 phosphorylation compared to wild-type EGF stimulation. Furthermore, the kinetics of EGFR activation by bivalent EGF differs from wild-type EGF with the appearance of a second activation peak at 20 minutes. Controlling the HER signaling network with these bivalent ligands has potential applications in tissue engineering, cancer therapy and in fundamental studies of the ErbB receptors activation mechanism

2009

Altered neocortical microcircuitry in the valproic acid rat model of autism

Tania Rinaldi

Autism is a wide-spectrum disorder with early childhood onset, affecting general cognitive capabilities and, in particular, complex information processing. Although interesting directions of research start to appear, the precise causes of the disorder and the resulting brain alterations have not been elucidated yet. The goal of this research project is to get a better understanding of the neocortical microcircuitry alterations in autism, using the valproic acid (VPA) rat model of autism. Exposure to VPA can cause several teratogenic effects, including autism in human if exposure occurs during the third week of gestation. Previous studies explored the results of prenatal VPA exposure in rats and found similar gross abnormalities to those in autism, such as diminished number of Purkinje cells. Behavioural studies further showed that a number of core symptoms, such as impairment in social interactions and higher sensitivity to sensory stimulation, are also present in the VPA-treated rats. We examined the postnatal effects of embryonic exposure to VPA on the microcircuitry properties of juvenile rat neocortex using in vitro electrophysiology. We found that prenatal VPA injection causes a significant increase of more than 50% of the local connectivity formed by pyramidal neurons of the somatosensory cortex, and that the neocortical network becomes hyper-reactive to external stimuli. We identify two possible compensatory mechanisms that may follow the observed hyperconnectivity: reduced excitability of pyramidal neurons and a decreased magnitude for individual synaptic connections. We also illustrate how NMDA receptors are significantly enhanced in the rat model and how this enhancement is associated with an increased plasticity in the neocortex. Both the somatosensorial and prefrontal cortex exhibit increased plasticity, suggesting a general enhanced plasticity in the brains of VPA-exposed rats. In addition, we show that multi-electrode array stimulation of the lateral amygdala reveals a hyper-reactive amygdala with increased synaptic plasticity. These alterations may account for some of the core symptoms in autism spectrum disorders. For example, hyperconnectivity could underlie symptoms such as aberrant reactions to sensory stimulation and altered attention. Also, the enhancement of NMDA mediated transmission and increased plasticity could explain the unusual learning and memory capabilities of some autistic children. Finally, we propose that the hyper-reactive and hyper-plastic amygdala underlies abnormal fear processing in this animal model of autism. We further speculate that abnormal fear processing could be a core pathology in autism which may give rise to behavioural symptoms, such as impairments in social interactions and resistance to rehabilitation.

EPFL2006

Altered neocortical microcircuitry in the valproic acid rat model of autism

Tania Rinaldi

EPFL2006