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Brodkin, E. S.

Publications and source records attributed to Brodkin, E. S..

2 recordsLinked to original sources

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

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.

neuroscience↗

Calculating the Effects of Autism Risk Gene Variants on Dysfunction of Biological Processes Identifies Clinically-Useful Information

Autism spectrum disorders (ASD) are neurodevelopmental conditions that are influenced by genetic factors and encompass a wide-range and severity of symptoms. The details of how genetic variation contributes to variable symptomatology are unclear, creating a major challenge for translating vast amounts of data into clinically-useful information. To determine if variation in ASD risk genes correlates with symptomatology differences among individuals with ASD, thus informing treatment, we developed an approach to calculate the likelihood of genetic dysfunction in Gene Ontology-defined biological processes that have significant overrepresentation of known risk genes. Using whole-exome sequence data from 2,381 individuals with ASD included in the Simons Simplex Collection, we identified likely damaging variants and conducted a clustering analysis to define subgroups based on scores reflecting genetic dysfunction in each process of interest to ASD etiology. Dysfunction in cognition-related genes distinguished a distinct subset of individuals with increased social deficits, lower IQs, and reduced adaptive behaviors when compared to individuals with no evidence of cognition-related gene dysfunction. In particular, a stop-gain variant in the pharmacogene encoding cycloxygenase-2 was associated with having an IQ<70 (i.e. intellectual disability), a key comorbidity in ASD. We expect that screening genes involved in cognition for deleterious variants in ASD cases may be useful for identifying clinically-informative factors that should be prioritized for functional follow-up. This has implications in designing more comprehensive genetic testing panels and may help provide the basis for more informed treatment in ASD.

genetics↗