Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

• Published in: Molecular psychiatry Vol. 23; no. 5; pp. 1356 - 1367
• Main Authors: Ung, D C, Iacono, G, Méziane, H, Blanchard, E, Papon, M-A, Selten, M, van Rhijn, J-R, Montjean, R, Rucci, J, Martin, S, Fleet, A, Birling, M-C, Marouillat, S, Roepman, R, Selloum, M, Lux, A, Thépault, R-A, Hamel, P, Mittal, K, Vincent, J B, Dorseuil, O, Stunnenberg, H G, Billuart, P, Nadif Kasri, N, Hérault, Y, Laumonnier, F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/44; 14/19; 14/28; 14/35; 38/39; 38/70; 38/90; 38/91; 45/41; 45/77; 631/378; 631/80; 64/110; 64/60; 692/699/476/1373; 82/80; 9/74; Animals; Autism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Behavioral Sciences; Biological Psychology; Cellular Biology; Cognition - physiology; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive science; Development and progression; Development Biology; Developmental disabilities; Disks Large Homolog 4 Protein - genetics; Disks Large Homolog 4 Protein - metabolism; EGR-1 protein; Gene expression; Gene regulation; Genetic aspects; Guanylate Kinases - genetics; Guanylate Kinases - metabolism; Health aspects; Hedgehog protein; Hippocampus - metabolism; Hyperactivity; Life Sciences; Male; Medicine; Medicine & Public Health; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mutation; Neurodevelopmental disorders; Neurogenetics; Neurons - metabolism; Neuroscience; Neurosciences; Original; original-article; Patched protein; Pharmacotherapy; Postsynaptic density proteins; Postsynaptic potentials; Protein structure; Proteins; Psychiatric research; Psychiatry; Signal Transduction; Synapses - genetics; Synapses - metabolism; Synaptic Transmission
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.39

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.