A Missense Variant at the Nrxn3 Locus Enhances Empathy Fear in the Mouse

Empathy is crucial for our emotional experience and social interactions, and its abnormalities manifest in various psychiatric disorders. Observational fear is a useful behavioral paradigm for assessing affective empathy in rodents. However, specific genes that regulate observational fear remain unknown. Here we showed that 129S1/SvImJ mice carrying a unique missense variant in neurexin 3 (Nrxn3) exhibited a profound and selective enhancement in observational fear. Using the CRISPR/Cas9 system, the arginine-to-tryptophan (R498W) change in Nrxn3 was confirmed to be the causative variant. Selective deletion of Nrxn3 in somatostatin-expressing (SST+) interneurons in the anterior cingulate cortex (ACC) markedly increased observational fear and impaired inhibitory synaptic transmission from SST+ neurons. Concordantly, optogenetic manipulation revealed that SST+ neurons in the ACC bidirectionally controlled the degree of socially transmitted fear. Together, these results provide insights into the genetic basis of behavioral variability and the neurophysiological mechanism controlling empathy in mammalian brains. [Display omitted] •The 129S1 mouse strain exhibits a selective enhancement in observational fear•A missense variant (R498W) in Nrxn3 causes elevation of observational fear•Selective deletion of Nrxn3 in SST+ neurons reduces GABA release in the ACC•SST+ inhibitory neurons in the ACC control the degree of socially transmitted fear Keum et al. demonstrate that a protein variant in the Nrxn3 gene causes an enhancement in observational fear and that Nrxn3-dependent inhibitory synaptic functions in somatostatin-positive interneurons in the anterior cingulate cortex control the degree of empathy fear.