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

L. P. Sowers, L. Loo, Y. Wu, E. Campbell, J. D. Ulrich, S. Wu, L. Paemka, T. Wassink, K. Meyer, X. Bing, H. El-Shanti, Y. M. Usachev, N. Ueno, R. J. Manak, A. J. Shepherd, P. J. Ferguson, B. W. Darbro, G. B. Richerson, D. P. Mohapatra, J. A. WemmieA. G. Bassuk

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1077-1089
Number of pages13
JournalMolecular Psychiatry
Volume18
Issue number10
DOIs
Publication statusPublished - Oct 2013

Fingerprint

Autistic Disorder
Genes
Wnt Signaling Pathway
Wnt Proteins
Post-Synaptic Density
Neurons
Interpersonal Relations
Dendrites
Synapses
Autism Spectrum Disorder
Siblings
Learning
Pathology
Phenotype
Brain

Keywords

  • autism
  • learning
  • memory
  • planar cell polarity
  • Wnt

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction. / Sowers, L. P.; Loo, L.; Wu, Y.; Campbell, E.; Ulrich, J. D.; Wu, S.; Paemka, L.; Wassink, T.; Meyer, K.; Bing, X.; El-Shanti, H.; Usachev, Y. M.; Ueno, N.; Manak, R. J.; Shepherd, A. J.; Ferguson, P. J.; Darbro, B. W.; Richerson, G. B.; Mohapatra, D. P.; Wemmie, J. A.; Bassuk, A. G.

In: Molecular Psychiatry, Vol. 18, No. 10, 10.2013, p. 1077-1089.

Research output: Contribution to journalArticle

Sowers, LP, Loo, L, Wu, Y, Campbell, E, Ulrich, JD, Wu, S, Paemka, L, Wassink, T, Meyer, K, Bing, X, El-Shanti, H, Usachev, YM, Ueno, N, Manak, RJ, Shepherd, AJ, Ferguson, PJ, Darbro, BW, Richerson, GB, Mohapatra, DP, Wemmie, JA & Bassuk, AG 2013, 'Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction', Molecular Psychiatry, vol. 18, no. 10, pp. 1077-1089. https://doi.org/10.1038/mp.2013.71
Sowers, L. P. ; Loo, L. ; Wu, Y. ; Campbell, E. ; Ulrich, J. D. ; Wu, S. ; Paemka, L. ; Wassink, T. ; Meyer, K. ; Bing, X. ; El-Shanti, H. ; Usachev, Y. M. ; Ueno, N. ; Manak, R. J. ; Shepherd, A. J. ; Ferguson, P. J. ; Darbro, B. W. ; Richerson, G. B. ; Mohapatra, D. P. ; Wemmie, J. A. ; Bassuk, A. G. / Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction. In: Molecular Psychiatry. 2013 ; Vol. 18, No. 10. pp. 1077-1089.
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