Age- and Sex-Specific Fear Conditioning Deficits in Mice Lacking Pcdh10, an Autism Associated Gene

Abstract

PCDH10 is a gene associated with Autism Spectrum Disorder. It is involved in the growth of thalamocortical projections and dendritic spine elimination. Previously, we characterized mice Pcdh10 haploinsufficient mice (Pcdh10+/− mice) and found male-specific social deficits that are rescued by N-methyl-D-aspartate receptor (NMDAR) partial agonist d-cycloserine, increased ultrasonic vocalizations in pups, and dark phase hypoactivity. In addition, we determined that the basolateral amygdala (BLA) of these mice exhibited increased dendritic spine density of immature morphology, decreased NMDAR expression, and decreased gamma synchronization. Here, we further characterize Pcdh10+/− mice by testing for fear memory, which relies upon BLA function. We used both male and female Pcdh10+/− mice and their wild-type littermates at two ages, juvenile and adult, and in two learning paradigms, cued and contextual fear conditioning. We found that males at both ages and in both assays exhibited fear conditioning deficits, but females were only impaired as adults in the cued condition. These data are further evidence for male-specific alterations in BLA-related behaviors in Pcdh10+/− mice, and suggest that these mice may be a useful model for dissecting male specific brain and behavioral phenotypes relevant to social and emotional behaviors.

ASD/OCD-Linked Protocadherin-10 Regulates Synapse, But Not Axon, Development in the Amygdala and Contributes to Fear- and Anxiety-Related Behaviors

“…Since PCDH10 is expressed in the NAc and mPFC as well, alterations in these connections may also contribute to the fear and anxiety phenotypes in Pcdh10 KO mice. Note that previously generated Pcdh10 LacZ/Neo heterozygous mice showed related but different behavioral phenotypes than our Pcdh10 KO mice (Schoch et al, 2017;Ferri et al, 2021). We posit that the behavioral phenotypes of Pcdh10 LacZ/Neo heterozygous mice may reflect the roles of PCDH10-expressing neurons affected by the LacZ/Neo cassette, but may not reflect the exact role of PCDH10 per se Involvement of PCDH10 in ASD, OCD, and MD The human PCDH10 gene has been linked to ASD, OCD, and MD (Morrow et al, 2008;Bucan et al, 2009;Qin et al, 2016;Roberson-Nay et al, 2020).…”