Neuropeptide S Receptor 1 variant (I107N) regulates behavioral characteristics and NPS effect in mice in a sex-dependent manner

Abstract

Accumulated data demonstrate that the A/T single-nucleotide polymorphism (SNP) rs324981 in the human neuropeptide S receptor 1 (NPSR1) gene, resulting in an amino acid change from asparagine (N) to isoleucine (I) at position 107, is associated with susceptibility to psychiatric disorders. Neuropeptide S (NPS) has also been implicated in modulating these disorders in rodent experiments. However, the effect of this SNP on NPSR1 activity remains unclear. To elucidate the pathophysiological and pharmacological implications of this SNP, we generated a mouse model carrying the human-specific AA variant in NPSR1. This model exhibited sex-specific behavioral differences mirroring human observations, including fear response, anxiety, and depression. Notably, intracerebroventricular administration of NPS (1 nmol) significantly promoted locomotor activity and alleviated looming-stimulated fear and anxiety-like behaviors in NPSR TT mice, but not in NPSR AA mice. NPS also reduced depression-like behavior in a sex and genotype-dependent manner in the forced swim test. Our study in NPSR variant mice enhances our understanding of phenotypic and pharmacological differences due to the NPSR1 SNP, providing an animal model for further investigation of physiological processes in humans carrying this SNP.