Journal article
Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction
Molecular psychiatry, Vol.18(10), pp.1077-1089
10/2013
DOI: 10.1038/mp.2013.71
PMCID: PMC4163749
PMID: 23711981
Abstract
Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that mice with disruption in
Prickle2
display behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility.
Prickle2
disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number, and post-synaptic density size. Consistent with these findings,
Prickle2
null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in
Prickle2
disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these
PRICKLE2
variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as
PRICKLE2
may contribute to synaptic abnormalities underlying ASDs.
Details
- Title: Subtitle
- Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction
- Creators
- L. P Sowers - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAL Loo - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAY Wu - Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAE Campbell - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAJ. D Ulrich - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAS Wu - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAL Paemka - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAT Wassink - Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAK Meyer - Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAX Bing - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAH El-Shanti - Shafallah Medical Genetics Center, Doha 33123, QatarY. M Usachev - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAN Ueno - Division of Morphogenesis, National institute for Basic Biology, Okazaki 444-8585, JapanR. J Manak - Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, IA 52242, USAA. J Shepherd - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAP. J Ferguson - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAB. W Darbro - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAG. B Richerson - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAD. P Mohapatra - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAJ. A Wemmie - Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USAA. G Bassuk - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.18(10), pp.1077-1089
- DOI
- 10.1038/mp.2013.71
- PMID
- 23711981
- PMCID
- PMC4163749
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Neurology; Psychiatry; Medical Genetics and Genomics; Surgery; Biology; Craniofacial Anomalies Research Center; Anesthesia; Rheumatology, Allergy, and Immunology; Molecular Physiology and Biophysics; Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Neurology (Pediatrics); Neurosurgery; Internal Medicine
- Record Identifier
- 9984013202802771
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