Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice.

Abstract

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (s₂R/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in s₂R/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of s₂R/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global <i>Tmem97</i> knock-out (KO) mice, we sought to identify the contribution of <i>Tmem97</i> in modulating affective and pain-like behaviors using a battery of affective and pain assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and the mechanical sensitivity tests. Our results demonstrate that female <i>Tmem97</i> KO mice show less anxiety-like and depressive-like behaviors in light/dark preference and tail suspension tests but not in an open field, elevated plus maze, and forced swim tests at baseline. We next performed spared nerve injury in WT and <i>Tmem97</i> KO mice to assess the role of <i>Tmem97</i> in neuropathic pain-induced anxiety and depression. WT mice, but not <i>Tmem97</i> KO mice, developed a prolonged neuropathic pain-induced depressive-like phenotype when tested 10 weeks after nerve injury in females. Our results show that <i>Tmem97</i> plays a role in modulating anxiety-like and depressive-like behaviors in naive animals with a significant change in the presence of nerve injury in female mice. Overall, these data demonstrate that <i>Tmem97</i> could be a target to alleviate affective comorbidities of pain disorders.