Chrna7 deficient mice manifest no consistent neuropsychiatric and behavioral phenotypes

Jiani Yin,Hongxing Yang,Wu Chen,Christian P Schaaf,Mingshan Xue

doi:10.1038/srep39941

Abstract

The alpha7 nicotinic acetylcholine receptor, encoded by the CHRNA7 gene, has been implicated in various psychiatric and behavioral disorders, including schizophrenia, bipolar disorder, epilepsy, autism, Alzheimer’s disease, and Parkinson’s disease, and is considered a potential target for therapeutic intervention. 15q13.3 microdeletion syndrome is a rare genetic disorder, caused by submicroscopic deletions on chromosome 15q. CHRNA7 is the only gene in this locus that has been deleted entirely in cases involving the smallest microdeletions. Affected individuals manifest variable neurological and behavioral phenotypes, which commonly include developmental delay/intellectual disability, epilepsy, and autism spectrum disorder. Subsets of patients have short attention spans, aggressive behaviors, mood disorders, or schizophrenia. Previous behavioral studies suggested that Chrna7 deficient mice had attention deficits, but were normal in baseline behavioral responses, learning, memory, and sensorimotor gating. Given a growing interest in CHRNA7-related diseases and a better appreciation of its associated human phenotypes, an in-depth behavioral characterization of the Chrna7 deficient mouse model appeared prudent. This study was designed to investigate whether Chrna7 deficient mice manifest phenotypes related to those seen in human individuals, using an array of 12 behavioral assessments and electroencephalogram (EEG) recordings on freely-moving mice. Examined phenotypes included social interaction, compulsive behaviors, aggression, hyperactivity, anxiety, depression, and somatosensory gating. Our data suggests that mouse behavior and EEG recordings are not sensitive to decreased Chrna7 copy number.

Highlights

To evaluate the putative role of Chrna7 in a variety of neuropsychiatric and behavioral phenotypes, we compared Chrna7 deficient mice of each sex with wildtype littermates, using a battery of 12 behavioral assays and EEG/EMG recordings
In an attempt to address whether CHRNA7 has an effect on repetitive behaviors and restricted interests, two of the core phenotypes of individuals with autism spectrum disorder, we tested homozygous and heterozygous Chrna7 deficient mice and their wildtype littermates in self-grooming, holeboard nose-poking, and marble burying tests
In the marble burying test (Fig. 1b), there was a significant effect from genotype x sex interaction, which came from the difference between KO and WT between the two sexes (Aligned rank transformation followed by Two-Way ANOVA, genotype effect F [2,75] = 0.26, P = 0.77; sex effect F [1,75] = 0.10, P = 0.33; sex x genotype F [2,75] = 4.32, *P = 0.02, post-hoc interaction analysis revealed difference between male: (KO-WT) and female: (KO-WT) F [1,11] = 8.48, multiple-test corrected *P = 0.01)

Summary

Introduction

To evaluate the putative role of Chrna7 in a variety of neuropsychiatric and behavioral phenotypes, we compared Chrna7 deficient mice of each sex with wildtype littermates, using a battery of 12 behavioral assays and EEG/EMG recordings. The marble burying test was used to evaluate repetitive digging behavior at 13 weeks of age, as described previously27, with the following modifications: corncob bedding was used, and a 30 min exploration period was allowed before mice were carefully removed from the cage and the number of marbles that were more than 50% buried were counted.

Results

Conclusion