Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Elisabeth F Raymond
Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Carole Gwizdek
Team SUMOylation in neuronal function and dysfunction, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Gihen Dhib
Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Gwenola Poupon
Team SUMOylation in neuronal function and dysfunction, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Laure-Emmanuelle Zaragosi
Team Physiological genomics of the eukaryotes, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
Emilie Pacary
INSERM U1215, Neurocentre Magendie, France et Université de Bordeaux, Bordeaux, France
Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, Nice, France
The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer’s disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.
