Abstract
The Sigma-2 receptor, recently identified as TMEM97, is a transmembrane protein that is located in the endoplasmic reticulum (ER) and the plasma membrane. Previous studies have shown that ligands that bind to TMEM97 have anxiolytic/antidepressant-like properties and relieve neuropathic pain in rodents. Despite medical interest in TMEM97, little to no affective and pain behavioral characterization has been done using transgenic mice, which hinders the development of TMEM97 as a viable therapeutic target. Using wild-type (WT) and global TMEM97 knockout (KO) mice, we aim to identify the contribution of TMEM97 in modulating affective and pain behaviors using a battery of affective and pain assays: open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and von Frey filaments test. Our results demonstrate that TMEM97 KO mice show less anxiety/depression-like behaviors in light/dark preference and tail suspension test but not in an open field, elevated plus maze, and forced swim test at baseline. We next performed spared nerve injury in WT and TMEM97 KO mice to assess the role of TMEM97 in neuropathic pain-induced anxiety and depression. Our animals were tested 10 weeks after nerve injury and developed pain-induced depression phenotype in WT but not in TMEM97 KO mice. Our results show that TMEM97 plays a role in modulating depression and anxiety in naïve animals with a significant change in the presence of nerve injury. Overall, these data demonstrate that TMEM97 can be targeted to alleviate pain-affective comorbidities. Funding: F31NS129269 National Institutes of Health under Grant No. F31NS129269.