Molecular origin of somatostatin-positive neuron vulnerability

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.