| First Author | Tomoda T | Year | 2022 |
| Journal | Mol Psychiatry | Volume | 27 |
| Issue | 4 | Pages | 2304-2314 |
| PubMed ID | 35145229 | Mgi Jnum | J:359606 |
| Mgi Id | MGI:7788555 | Doi | 10.1038/s41380-022-01463-4 |
| Citation | Tomoda T, et al. (2022) Molecular origin of somatostatin-positive neuron vulnerability. Mol Psychiatry 27(4):2304-2314 |
| abstractText | Reduced somatostatin (SST) and dysfunction of SST-positive (SST(+)) neurons are hallmarks of neurological disorders and associated with mood disturbances, but the molecular origin of SST(+) neuron vulnerability is unknown. Using chronic psychosocial stress as a paradigm to induce elevated behavioral emotionality in rodents, we report a selective vulnerability of SST(+) neurons through exacerbated unfolded protein response (UPR) of the endoplasmic reticulum (ER), or ER stress, in the prefrontal cortex. We next show that genetically suppressing ER stress in SST(+) neurons, but not in pyramidal neurons, normalized behavioral emotionality induced by psychosocial stress. In search for intrinsic factors mediating SST(+) neuron vulnerability, we found that the forced expression of the SST precursor protein (preproSST) in SST(+) neurons, mimicking psychosocial stress-induced early proteomic changes, induces ER stress, whereas mature SST or processing-incompetent preproSST does not. Biochemical analyses further show that psychosocial stress induces SST protein aggregation under elevated ER stress conditions. These results demonstrate that SST processing in the ER is a SST(+) neuron-intrinsic vulnerability factor under conditions of sustained or over-activated UPR, hence negatively impacting SST(+) neuron functions. Combined with observations in major medical illness, such as diabetes, where excess ER processing of preproinsulin similarly causes ER stress and beta cell dysfunction, this suggests a universal mechanism for proteinopathy that is induced by excess processing of native endogenous proteins, playing critical pathophysiological roles that extend to neuropsychiatric disorders. |
