Aperçu: G.M.
Le
développement de la synapse et l'activité neuronale représentent des
processus fondamentaux pour l'établissement de la fonction cognitive. L'organisation
structurale ainsi que les voies de signalisation allant de la
stimulation des récepteurs à la régulation de l'expression des gènes
sont médiées par l'activité synaptique et mal interprétées dans les
troubles du développement neurologique tels que le trouble du spectre
de l'autisme (TSA) et la déficience intellectuelle (DI).
Des
mutations délétères dans le gène PTCHD1 ont été décrites chez des patients mâles avec une DI ou un TSA lié à l'X.
Les résultats confirment que la carence en PTCHD1 induit un trouble du développement
neurologique entraînant une dysfonction synaptique excitatrice.
Mol Psychiatry. 2017 Apr 18. doi: 10.1038/mp.2017.39.
Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse
Ung DC1,2, Iacono G3, Méziane H4, Blanchard E1,5,6, Papon MA1,2, Selten M7, van Rhijn JR7, Montjean R8,9,10,11, Rucci J8,9,10,11, Martin S12, Fleet A13, Birling MC4, Marouillat S1,2, Roepman R14,15, Selloum M4, Lux A4, Thépault RA1,2, Hamel P13, Mittal K16, Vincent JB16, Dorseuil O8,9,10,11, Stunnenberg HG3, Billuart P8,9,10,11, Nadif Kasri N7,14, Hérault Y4,17,18,19,20, Laumonnier F1,2,6.
Author information
- 1
- University François-Rabelais, UMR Imaging and Brain, Tours, France.
- 2
- Institut National de la Santé et de la Recherche Médicale, U930, Tours, France.
- 3
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
- 4
- CELPHEDIA PHENOMIN, Institut Clinique de la Souris (ICS), CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden, France.
- 5
- Institut National de la Santé et de la Recherche Médicale, U966, Tours, France.
- 6
- Centre Hospitalier Régional Universitaire, Tours, France.
- 7
- Department of Cognitive Neuroscience, Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
- 8
- Institut Cochin, 24 rue du Fg St Jacques, Paris, France.
- 9
- Institut National de la Santé et de la Recherche Médicale, U1016 Paris, France.
- 10
- Centre National de la Recherche Scientifique, UMR8104, Paris, France.
- 11
- University Paris Descartes, Institut Cochin, Paris, France.
- 12
- Université Côte d'Azur, INSERM, CNRS, IPMC, France.
- 13
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- 14
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
- 15
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
- 16
- Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
- 17
- Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch, Illkirch-Graffenstaden, France.
- 18
- University of Strasbourg, Illkirch, France.
- 19
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
- 20
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, 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.Molecular Psychiatry advance online publication, 18 April 2017; doi:10.1038/mp.2017.39.
- PMID: 28416808
- DOI: 10.1038/mp.2017.39
