ABSTRACT
Title
ADAM10 regulates spine morphology and glutamate receptor composition through N-Cadherin cleavage
Authors
M. Malinverno,1 F. Gardoni,1 M. Carta,2 R. Epis,1,4 E. Marcello,1 C. Verpelli,3 F. Cattabeni,1 C. Sala,3 C. Mulle2 and M. Di Luca1
1Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy, 2Laboratoire Physiologie Cellulaire de la Synapse, Centre National de la Recherche Scientifique Unite´ Mixte de Recherche 5091, Bordeaux Neuroscience Institute, University of Bordeaux 2, 33077 Bordeaux, France,
3Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, and 4XigenPharma, 1003 Lausanne, Switzerland
1Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy, 2Laboratoire Physiologie Cellulaire de la Synapse, Centre National de la Recherche Scientifique Unite´ Mixte de Recherche 5091, Bordeaux Neuroscience Institute, University of Bordeaux 2, 33077 Bordeaux, France,
3Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, and 4XigenPharma, 1003 Lausanne, Switzerland
Abstract
Cell-cell adhesion molecule N-cadherin is crucial in several physiological events such as synapse formation during neuronal development and activity-dependent spine remodelling. Recently, it has been shown that ADAM10 (a disintegrin and metalloproteinase 10) is involved in N-Cadherin processing occurring at the membrane level. Here we demonstrate that activation of ADAM10 in hippocampal neurons leads to an increased N-Cadherin cleavage paralleled by a significant reduction of dendritic spine size. Conversely, inhibition of ADAM10 localization at synaptic sites, by using a cell-permeable peptide able to disrupt the interaction with its cargo protein SAP97, leads to a decreased ADAM10 mediated N-Cadherin processing. This event is paralleled by a significant increase of dendritic spine size and AMPA receptor GluR1 subunit levels at synapse. Overall, our data show that ADAM10 plays an important role in spine remodelling as well as AMPA receptor composition and functioning during the highly regulated neurodevelopmental events of the glutamatergic synapse.