Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non- canonical Wnt signaling pathways;still, no human variant in Wnt-pathway genes have been connected directly to ASD-relevant brain pathology. Recently, however, we discovered two families with ASD-specific mutations in PRICKLE2 (PK2). In vitro, recombinant mutant PK2s displayed a lowered affinity for PSD-95, another protein implicated in ASDs. Moreover, hippocampal neurons isolated from Prickle2-null (Pk2-/-) mice assumed an abnormal morphology and generated less spontaneous quantal synaptic activity;in complementation assays, these defects in hippocampal neurons were not rescued with the mutant forms of human PK2, suggesting these mutants lacked critical functions. Further behavioral studies in Pk2-/- mice showed their behavior mirrored ASD-like behaviors in humans. These studies provide new insight into the biological roles of PRICKLE2, its behavioral importance, and more firmly link Wnt-signaling abnormalities to ASDs. Our preliminary findings led us to the hypothesis that Wnt-modulating reagents represent an unexplored class of ASD treatments. Our long-term goals are to develop safer and more effective drug regimens for treating ASDs. The objective of this R21 application is to determine whether Wnt-modulating reagents alleviate the synaptic abnormalities observed in Pk2-/- neurons and the ASD-associated behaviors in Pk2-/- mice. The studies proposed here should both further our understanding of the biology of Wnt signaling and its connection to behavior, and lead to new therapeutic modalities. !

Public Health Relevance

Autism Spectrum Disorders (ASDs) are defined by impairments in social interactions, learning, and behavioral flexibility. Recently, the United States Center for Disease Control (CDC) reported that ASD develops in one of every 88 children born in the US, a rate that has continually climbed, highlighting the need to develop effective treatment and prevention strategies. Our long-term goals are to develop safer and more effective drug regimens for treating ASDs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH100086-01
Application #
8476485
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Asanuma, Chiiko
Project Start
2013-06-11
Project End
2015-05-31
Budget Start
2013-06-11
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$184,568
Indirect Cost
$59,568
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mei, Xue; Westfall, Trudi A; Zhang, Qihong et al. (2014) Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms. Dev Biol 392:245-55
Yin, Terry C; Britt, Jeremiah K; De Jesús-Cortés, Héctor et al. (2014) P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury. Cell Rep 8:1731-40