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

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.

The Planar Cell Polarity Transmembrane Protein Vangl2 Promotes Dendrite, Spine and Glutamatergic Synapse Formation in the Mammalian Forebrain

“…In line with this, several PCP proteins contributing to these processes have been implicated in psychiatric pathophysiology. For example, in mice, the elimination of Dvl1 reduces social behavior [44] and Prickle2 sequence variants associated with autism lead to dendrite and glutamatergic synapse phenotypes [45]. Our work with Vangl2 accords with these findings and underscores that at some genetic loci and in some biochemical pathways different molecular defects can lead to similar neural phenotypes.…”

Control of vertebrate core PCP protein localization and dynamics by Prickle2

“…Ultimately, this work provides a foundation for future studies into the role of vertebrate Pk proteins, and thus might help to elucidate the etiology of Pk-associated human pathologies, such as epilepsy, congenital birth defects and, possibly, autism (Okumura et al, 2014;Sowers et al, 2013;Tao et al, 2011;Wen et al, 2010).…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…There are numerous studies, primarily in gene-targeted mouse lines, demonstrating that genetic disruption in Wnt pathway genes can affect complex behavior, including in assays of sociability, repetitive behaviors and vocalizations that could be relevant to the cardinal symptoms of ASD [237,238,239,240,241,242], sensory processing and prepulse inhibition that could be relevant to symptoms of Scz [243,244,245], and motivation, impulsivity, anxiety and activity patterns that could be relevant to symptoms of BD and other affective and anxiety disorders [246,247,248](Table 8). These data clearly demonstrate behavioral phenotypes in these animal models, but controversy remains over the relevance of such findings to the genetic etiology of psychiatric disorders - that is, it remains unclear whether such data have predictive relevance for involvement of the corresponding genes in clinically defined behavioral disorders in the human population.…”