1. Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse
- Author
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Ung, D., Iacono, G, Méziane, H, Blanchard, E., Papon, M-A, Selten, M, van Rhijn, J-R, Montjean, R, Rucci, J, Martin, Stéphane, Fleet, A, Birling, M-C, Marouillat, S, Roepman, R, Selloum, M, Lux, A., Thépault, R-A, Hamel, P, Mittal, K, Vincent, J., Dorseuil, O, Stunnenberg, H, Billuart, P, Nadif Kasri, N, Hérault, Y., Laumonnier, F, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud university [Nijmegen], Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Donders Institute for Brain, Cognition and Behaviour, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), University of Toronto, Radboud University Medical Center [Nijmegen], Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Martin, Stephane, Radboud University [Nijmegen], and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
- Subjects
Male ,[SDV]Life Sciences [q-bio] ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Hippocampus ,Synaptic Transmission ,Mice ,[SCCO]Cognitive science ,Cognition ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Cognitive Dysfunction ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Molecular Biology ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Neurons ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SCCO.NEUR] Cognitive science/Neuroscience ,Membrane Proteins ,[SCCO] Cognitive science ,[SDV] Life Sciences [q-bio] ,Mice, Inbred C57BL ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Synapses ,Original Article ,Disks Large Homolog 4 Protein ,Guanylate Kinases ,Signal Transduction - Abstract
Contains fulltext : 193089.pdf (Publisher’s version ) (Open Access) Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1(-/y)) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.
- Published
- 2018
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