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 β 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.
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The authors thank Mohan Pabba, Rammohan Shukla, Mounira Banasr, Thomas Prevot, and Hyunjung Oh for comments or discussion. This work was supported by grants from the Canadian Institute of Health Research (CIHR #153175 to ES), National Alliance for Research on Schizophrenia and Depression (NARSAD award #25637 to ES), the National Institutes of Health (MH-093723 to ES), Campbell Family Mental Health Research Institute (to ES).
The authors declare no competing interests.
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Tomoda, T., Sumitomo, A., Newton, D. et al. Molecular origin of somatostatin-positive neuron vulnerability. Mol Psychiatry 27, 2304–2314 (2022). https://doi.org/10.1038/s41380-022-01463-4