Quantification of Behavioral Deficits in Developing Mice With Dystonic Behaviors.

Authors

Meike E Van Der Heijden
Jason S Gill
Alejandro G Rey Hipolito
Luis E Salazar Leon
Roy V Sillitoe

Publication Date

1-1-2022

Journal

Dystonia

DOI

10.3389/dyst.2022.10494

PMID

36960404

PMCID

PMC10032351

PubMedCentral® Posted Date

3-22-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

dystonia, cerebellum, behavior, development, neurodevelopmental disorders

Abstract

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. Here, we characterize the early-onset dystonia in Ptf1aCre;Vglut2fl/fl mice, which is caused by the absence of neurotransmission from inferior olive neurons onto cerebellar Purkinje cells. We investigate motor control with two paradigms that examine how altered neural function impacts key neurodevelopmental milestones seen in postnatal pups (postnatal day 7–11). We find that Ptf1aCre;Vglut2fl/fl mice have poor performance on the negative geotaxis assay and the surface righting reflex. Interestingly, we also find that Ptf1aCre;Vglut2fl/fl mice make fewer ultrasonic calls when socially isolated from their nests. Ultrasonic calls are often impaired in rodent models of autism spectrum disorders, a condition that can be comorbid with dystonia. Together, we show that these assays can serve as useful quantitative tools for investigating how neural dysfunction during development influences neonatal behaviors in a dystonia mouse model. Our data implicate a shared cerebellar circuit mechanism underlying dystonia-related motor signs and social impairments in mice.