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Mol Psychiatry. 2018 May;23(5):1356-1367. doi: 10.1038/mp.2017.39. Epub 2017 Apr 18.

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse.

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.

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