Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

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.

Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity

“…The first dataset we assessed was obtained from Ptchd1 -KO mice. Loss-of-function mutations in the PTCHD1 gene lead to X-linked intellectual disability (OMIM # 300830) ( Ung et al, 2017 ). We found that nearly 23% (185 genes) of the genes that are downregulated in the hippocampus of Ptchd1 -KO mice are amongst the genes that increase following DBS in WT mice ( Figure 7A ).…”

“…Limma ( Ritchie et al, 2015 ), a R package was used for differential expression analysis and genes with FDR < 0.05 and absolute logFC >0 were called as differentially expressed and were used for further analysis. For Intellectual Disorder, we used list of differentially expressed downregulated genes from the following studies ( Mehmood et al, 2011 ; Ung et al, 2017 ).…”

Cellular Functions of the Autism Risk Factor PTCHD1 in Mice

“…In situ hybridization and PCR analysis. In situ hybridizations with chromogenic detection were done using digoxigenin-labeled cRNA probes and were performed as described previously (Schaeren-Wiemers and Gerfin-Moser, 1993). The DNA fragment encoding the Ptchd1 probe contained SP6 and T7 promoters flanking the 5Ј-or 3Ј-end, respectively: Ptchd1:CCGCTCTGCTCTAGGATGCTGCGGCAGGTTCTGCACAGG GGCTTGAGGACGTGTTTCTCCCGGCTTGGCCACTTCATTGCCA GTCACCCGGTCTTCTTTGCTTCGGCGCCGGTGCTCATCTCCAT CCTGCTCGGCGCCAGCTTCAGCCGCTACCAGGTCGAAGAGAGC GTGGAGCACCTGCTGGCGCCCCAGCACAGCCTAGCCAAGATCG AGCGCAACCTAGTCAACAGCCTCTTCCCGGTCAACCGCTCCAAG CACCGGCTCTACTCGGACCTGCAGACCCCTGGGCGCTACGGCC GGGTCATTGTCACCTCCTACCAGAAAGCCAACATGCTAGACC AACATCACACGGACCTGA.…”

Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

“…PTCHD1 encodes a transmembrane protein with a patched domain, and its involvement in neurodevelopmental disorders is supported by microdeletions and frameshift mutations in individuals with neurodevelopmental delay (NDD), intellectual disability, and ASD (15)(16)(17)(18)(19)(20)(21). However, recently described Ptchd1 mutant mice had impairments in attention and cognition (22)(23)(24) but did not overtly exhibit ASD-associated behaviors. Also, many ASDassociated PTCHD1 locus microdeletions are upstream of the PTCHD1 protein-coding gene and disrupt exons of the neighboring brain-enriched long noncoding RNA (lncRNA) PTCHD1-AS (15).…”