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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
1 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
2 Radboud university [Nijmegen]
3 ICS - Institut Clinique de la Souris
4 MAVIVH - U1259 Inserm - CHRU Tours - Morphogénèse et antigénicité du VIH et du virus des Hépatites
5 Donders Institute for Brain, Cognition and Behaviour
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 IPMC - Institut de pharmacologie moléculaire et cellulaire
8 University of Toronto
9 Radboud University Medical Center [Nijmegen]
10 Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands]
11 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)
12 Inserm U964 - CNRS UMR7104 - IGBMC - Centre for Integrative Biology - CBI
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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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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