Alteration of empathy-related behaviors in two strains of mice expressing mutations of the α5 cholinergic nicotinic receptor subunit

A single nucleotide polymorphism (SNP) of the alpha5 subunit of nicotinic acetylcholine receptors (nAChRs) increases human risk for nicotine dependence, alcohol use disorders (AUDs), and schizophrenia. Here, we used transgenic mice carrying either this SNP (rs16969968; α5SNP/α5KI) or a Chrna5 knockout (α5KO) to examine the role of α5-containing nAChRs in affective state discrimination and prosocial, rescuing-like behaviors. α5KO mice failed to recognize a negative affective state in a familiar peer and displayed severely altered prosocial, empathy-related behaviors, at times assaulting distressed peers. In contrast, α5KI mice discriminated affective states normally and showed increased rescuing-like behavior. Effects of α5 mutations on affective state discrimination were sex stratified. These findings demonstrate the critical implication of α5∗nAChRs in affective state discrimination and prosocial-like behaviors, revealing sex-stratified patterns of these social-emotional deficits in α5KI and α5KO mice, which are reminiscent of the behavioral features of two characterized subtypes of AUD in humans.