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Journal articles
Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse
D. Ung
1
G Iacono
2
H Méziane
3
E. Blanchard
4
M-A Papon
1
M Selten
5
J-R van Rhijn
5
R Montjean
6
J Rucci
6
Stéphane Martin
7
A Fleet
8
M-C Birling
3
S Marouillat
1
R Roepman
9, 10
M Selloum
3
A. Lux
3
R-A Thépault
1
P Hamel
8
K Mittal
11
J. Vincent
11
O Dorseuil
6
H Stunnenberg
2
P Billuart
6
N Nadif Kasri
5, 9
Y. Hérault
3, 12, *
F Laumonnier
1, *
*
Corresponding author
J Rucci 6
Author
Stéphane Martin 7
Mail :
Author Employer institution : Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis IdHAL : stef-martin ResearcherId : http://www.researcherid.com/rid/G-5954-2012 ORCID : https://orcid.org/0000-0001-6771-7645
A Fleet 8
Author
M-C Birling 3
Author
Y. Hérault 3, 12
Mail :
Correspondent author
F Laumonnier 1
Mail :
Correspondent author
1
Imagerie et cerveau (CHRU de Tours - Hôpital Bretonneau
2 boulevard Tonnellé
Bâtiment B1A, 1er étage
37044 Tours Cedex 9 France - France)
- Université de Tours : U930 (60 rue du Plat d'Étain, 37020 Tours cedex 1 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U930 (101, rue de Tolbiac, 75013 Paris - France)
2
Radboud university [Nijmegen] (Comeniuslaan 4, 6525 HP Nijmegen - Netherlands)
3
ICS - Institut Clinique de la Souris (Génopole de Strasbourg 67404 Illkirch Cedex - France)
- UNISTRA - Université de Strasbourg (4 rue Blaise Pascal - CS 90032 - 67081 Strasbourg cedex - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U (101, rue de Tolbiac, 75013 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : UMR (France)
4
MAVIVH - Morphogénèse et antigénicité du VIH et du virus des Hépatites (Faculté de Médecine - 10 boulevard Tonnellé - BP 3223 - 37032 Tours Cedex 1 - France)
- CHRU Tours - Centre Hospitalier Régional Universitaire de Tours (France)
- Université de Tours (60 rue du Plat d'Étain, 37020 Tours cedex 1 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U966 (101, rue de Tolbiac, 75013 Paris - France)
5
Donders Institute for Brain, Cognition and Behaviour (Montessorilaan 3
6525 HR Nijmegen
The Netherlands - Netherlands)
- Radboud university [Nijmegen] (Comeniuslaan 4, 6525 HP Nijmegen - Netherlands)
6
IC UM3 (UMR 8104 / U1016) - Institut Cochin (22 rue Méchain, 75014 Paris - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1016 (101, rue de Tolbiac, 75013 Paris - France)
- UPD5 - Université Paris Descartes - Paris 5 : UM 3 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- CNRS - Centre National de la Recherche Scientifique : UMR 8104 (France)
7
IPMC - Institut de pharmacologie moléculaire et cellulaire (CNRS-IPMC 660 Route des lucioles 06560 VALBONNE - France)
- UNS - Université Nice Sophia Antipolis (... - 2019) (Parc Valrose - BP 2135 - 06103 Nice cedex 2 - France)
- COMUE UCA - COMUE Université Côte d'Azur (2015 - 2019) (Parc Valrose, 28 avenue Valrose 06108 Nice Cedex 2 - France)
- CNRS - Centre National de la Recherche Scientifique : UMR6097 (France)
8
University of Toronto (27 King's College Circle, Toronto M5S 1A1 - Canada)
9
Radboud University Medical Center [Nijmegen] (P.O. Box 9101
6500 HB Nijmegen - Netherlands)
11
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH) (Canada)
12
Inserm U964 - CNRS UMR7104 - IGBMC - Centre for Integrative Biology - CBI (France)
- UNISTRA - Université de Strasbourg (4 rue Blaise Pascal - CS 90032 - 67081 Strasbourg cedex - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U964 (101, rue de Tolbiac, 75013 Paris - France)
- Institute of genetics and molecular and cellular biology (Illkirch - France)
- CNRS - Centre National de la Recherche Scientifique : UMR7104 (France)
Abstract : 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.
Document type :
Journal articles
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https://www.hal.inserm.fr/inserm-02443532
Contributor : Stephane Martin <>
Submitted on : Friday, January 17, 2020 - 11:26:55 AM
Last modification on : Tuesday, May 26, 2020 - 6:50:15 PM
Contributor : Stephane Martin <>
Submitted on : Friday, January 17, 2020 - 11:26:55 AM
Last modification on : Tuesday, May 26, 2020 - 6:50:15 PM
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Identifiers
- HAL Id : inserm-02443532, version 1
- DOI : 10.1038/mp.2017.39
- PUBMED : 28416808
- PUBMEDCENTRAL : PMC5984103
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IGBMC | UNIV-PARIS5 | SITE-ALSACE | UNIV-TOURS | USPC | CNRS | UGA | UP-SANTE | UNICE | UNIV-COTEDAZUR
Citation
D. Ung, G Iacono, H Méziane, E. Blanchard, M-A Papon, et al.. Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse. Molecular Psychiatry, Nature Publishing Group, 2018, 23 (5), pp.1356-1367. ⟨10.1038/mp.2017.39⟩. ⟨inserm-02443532⟩
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