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Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Molecular Psychiatry volume 18, pages 1077–1089 (2013)Cite this article

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A Corrigendum to this article was published on 05 November 2013

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 PSD 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.

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Acknowledgements

Thanks to Dr Margaret Price, Michael Lutter, Jeff Murray, Mathew State and Dr Vinu Mahajan for comments and insights regarding the paper. Thanks to Chantal Allamargot and Jean Ross in the University of Iowa Microscopy core for their technical assistance. This work was supported by NIH grant 1R01 NS064159-01A1 and a University of Iowa ICTS pilot-award (AGB).

Author contributions

LPS contributed to all experiments, planning and writing of the paper. LL performed all in vitro electrophysiology. YW performed in vivo electrophysiology. LL, LPS and DPM analyzed all the electrophysiology data. EC performed mouse behavioral experiments. YMU and JU performed a part of primary hippocampal neuron cultures. SW performed western blot experiments. JRM, HEL, LP, TW, XY and KM aided in the collection and sequencing of human DNA. PF, NU and SW conducted production and breeding of mice of different genotypes used in this study. AJS assisted in all immunocytochemistry experiments and analysis. GBR, DPM and JM provided reagents, supervised experiments and analysis, and aided in manuscript writing. JAW provided all behavioral equipment. JAW and DPM provided scientific input to the study design. BWD provided statistical analysis for whole-exome sequencing data. All authors contributed to the writing of this manuscript. AGB supervised all aspects of the project design, execution and writing of the paper. The data sets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000298.v1.p1, under dbGAP Research Project #4357 (Variation in PRICKLE2 and related Genes in Autism) to AGB. The data set(s) were deposited by the ARRA Autism Sequencing Collaborative, an ARRA funded research initiative. Support for the Autism Sequencing Collaborative was provided by grants: R01-MH089208 awarded to Dr Mark Daly, R01-MH089175 awarded to Dr Richard Gibbs, R01-MH089025 awarded to Joseph Buxbaum, R01-MH089004 awarded to Gerard Schellenberg and R01-MH089482 awarded to James Sutcliffe. Embargo release date for the data was 29 February 2013.

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Authors and Affiliations

  1. Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

    L P Sowers, E Campbell, S Wu, L Paemka, X Bing, P J Ferguson, B W Darbro, G B Richerson & A G Bassuk

  2. Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, IA, USA

    L P Sowers, R J Manak, G B Richerson & A G Bassuk

  3. Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

    L Loo, J D Ulrich, Y M Usachev, A J Shepherd & D P Mohapatra

  4. Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

    Y Wu & G B Richerson

  5. Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA, USA

    L Paemka, R J Manak & A G Bassuk

  6. Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

    T Wassink, K Meyer & J A Wemmie

  7. Shafallah Medical Genetics Center, Doha, Qatar

    H El-Shanti

  8. Interdisciplinary Graduate Program in Neuroscience, The University of Iowa, Iowa City, IA, USA

    Y M Usachev, G B Richerson, D P Mohapatra, J A Wemmie & A G Bassuk

  9. Division of Morphogenesis, National Institute for Basic Biology, Okazaki, Japan

    N Ueno

  10. Department of Biology, The University of Iowa, Iowa City, IA, USA

    R J Manak

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  1. L P Sowers
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  2. L Loo
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Correspondence to A G Bassuk.

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Sowers, L., Loo, L., Wu, Y. et al. Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction. Mol Psychiatry 18, 1077–1089 (2013). https://doi.org/10.1038/mp.2013.71

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