Developmental pyrethroid exposure in the Shank3 mutant prairie vole as a 2-hit model for neurodevelopmental disorder risk

Project Summary
The prevalence of autism and other neurodevelopmental disorders (NDDs) is at an all-time high, with 17% of
children diagnosed with a developmental disability and 1 in 44 diagnosed with autism. Many of these disorders
have few or no established biomarkers, few or no medical treatments, and can only be diagnosed behaviorally,
emphasizing the need for research into causes and treatments. Furthermore, the vast majority of cases of
autism arise from multiple genetic and environmental causes, with less than 10% of cases having a single
identifiable cause. There is a critical knowledge gap regarding the way genetic and environmental risk factors
interact to contribute to risk for autism and other NDDs, and a critical need for animal models that incorporate
more than one type of risk factor.
Exposure to pyrethroid pesticides during pregnancy is an environmental risk factor for autism and NDDs.
Pyrethroids are among the most common pesticides in the US and are present in 70-80% of blood samples
from the general public. Nonetheless, multiple epidemiology studies have linked pyrethroid exposure during
pregnancy with autism and developmental delay in the child, and the presence of pyrethroid metabolites in the
blood predicts ADHD diagnosis.
The Shank3 gene is a prominent autism-associated gene, both because of evidence linking human Shank3
dysfunction to autism and 22q13 deletion syndrome. Shank3 mutations in mouse and rat lines lead to deficits
in social interaction, social communication, repetitive behaviors, and circadian rhythms, and preliminary data
shows that the Shank3 heterozygous (+/-) prairie vole has similar deficits in social interaction.
We propose to study the interaction of these two autism risk factors using the prairie vole, a wild rodent
species bred in the laboratory which has a unique set of complex species-specific behaviors similar to humans,
including monogamous bonding, biparental care, and consoling behavior. We will pair prairie vole mothers with
a Shank3 heterozygous father, and then expose the mother to low doses of the pyrethroid pesticide
deltamethrin during pregnancy and lactation. We will then study both wild-type and Shank3 offspring to assess
deficits in autism-relevant behaviors in the social, communication, cognition, repetitive behavior, and locomotor
domains. We will simultaneously assess biological changes in the brain, focusing on the MAPK/mTOR
signaling pathways, which are modulated by Shank3 and are altered in developmental pyrethroid exposure.
Successful completion of these Aims will inform about the interaction between two autism risk factors, Shank3
haploinsufficiency and developmental pyrethroid exposure. This will provide the starting point for a line of
research focusing on combined autism risk from multiple risk factors within a single animal model using
complex social behaviors as primary outcomes.

Grant Number: 1R21ES036352-01A1
NIH Institute/Center: NIH
Principal Investigator: James Burkett