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

• Published in: Molecular psychiatry Vol. 18; no. 10; pp. 1077 - 1089
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2013; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/378/548; 692/699/476/1312; Amino Acid Sequence; Animal models; Animals; Autism; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Cells, Cultured; Child clinical studies; Child Development Disorders, Pervasive - genetics; Child Development Disorders, Pervasive - physiopathology; Child Development Disorders, Pervasive - psychology; Conditioning, Classical; Dendrites - ultrastructure; Dendritic branching; Developmental disorders; Diagnosis; Exploratory Behavior; Fear; Female; Freezing Reaction, Cataleptic - physiology; Genetic aspects; Hippocampus; Hippocampus (Brain); Hippocampus - pathology; Hippocampus - physiopathology; Humans; Infantile autism; LIM Domain Proteins - deficiency; LIM Domain Proteins - genetics; LIM Domain Proteins - physiology; Male; Maze Learning; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Miniature Postsynaptic Potentials - genetics; Mutation, Missense; Neurons - pathology; Neurons - physiology; Neurosciences; original-article; Pervasive developmental disorders; Pharmacotherapy; Phenotype; Phenotypes; Physiological aspects; Point Mutation; Post-Synaptic Density - pathology; Postsynaptic density proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Recombinant Fusion Proteins - metabolism; Sequence Homology, Amino Acid; Signal transduction; Social Behavior; Social discrimination learning; Synaptic density; Wnt protein; Wnt proteins; Wnt Signaling Pathway; United States; learning; memory; planar cell polarity; Wnt; autism; Human; Animal model; Memory; Rodentia; Central nervous system; Developmental disorder; Signalling; Genetic determinism; Encephalon; Behavioral disorder; Learning; Autism; Vertebrata; Mammalia; Acquisition process; Mouse; Animal; Genetics; Polarity; Hippocampus
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.71

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.