The insertion of Neomycin cassette impairs maternal and social behaviors in Arc/Arg3.1 knock-out mice

TL;DR

This study shows that the Neomycin cassette insertion in Arc/Arg3.1 knockout mice causes significant social and maternal behavior impairments, highlighting the importance of considering genetic construct effects in behavioral neuroscience research.

Contribution

It demonstrates that the Neo cassette itself, not just gene deletion, can impair social behaviors and alter neurobiological pathways in knockout mice.

Findings

Neo+ mice show severe maternal behavior deficits

Altered ERK signaling and oxytocin system in Neo+ mice

Environmental enrichment improves social interaction with familiar conspecifics

Abstract

The Neomycin resistance cassette (Neo+) is commonly inserted in the genome of mice to generate knock-out (KO) models. The effect of gene deletion on social behaviors in mice is controversial between studies using different Neo+ and Neo-mouse lines, particularly Arc/Arg3.1 KO lines. In this study, we identified severe maternal behavior impairments in Neo+, but not Neo-Arc/Arg3.1 KO dams. These deficits resulted from reduced sociability and abnormal social information processing in Neo+ Arc/Arg3.1 KO dams, exacerbated by social communication impairments in pups. The expression of the Neo cassette product did not cause cytotoxicity, but led to altered ERK signaling, gene expression, and oxytocin system. However, oxytocin administration did not improve social impairments in Neo+ Arc/Arg3.1 KO animals. Interestingly, early social environment enrichment enhanced social interaction with familiar, but not unfamiliar conspecifics or maternal behavior. Overall, our findings reveal a major impact of the Neo cassette on behaviors, particularly social behaviors, in Arc/Arg3.1 KO mice, underscoring the need to re-examine phenotypes of animal models carrying the Neo cassette in neuroscience research.