PT  - JOURNAL ARTICLE
AU  - Tomoda, Toshifumi
AU  - Sumitomo, Akiko
AU  - Newton, Dwight
AU  - Sibille, Etienne
TI  - Molecular origin of somatostatin-positive neuron vulnerability
AID  - 10.1101/2021.02.16.431515
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.16.431515
4099  - http://biorxiv.org/content/early/2021/02/17/2021.02.16.431515.short
4100  - http://biorxiv.org/content/early/2021/02/17/2021.02.16.431515.full
AB  - Reduced somatostatin (SST) and SST-positive (SST+) neurons are hallmarks of neurological disorders and associated with mood disturbances, but their origin are unknown. Chronic psychosocial stress induces behavioral emotionality deficits and deregulates unfolded protein response (UPR) of the endoplasmic reticulum (ER) preferentially in SST+ neurons. Here we confirm that chronic stress increases ER stress levels in SST+ neurons of mouse prefrontal cortex, and show that genetically suppressing ER stress in SST+ neurons, but not in pyramidal neurons, normalized psychosocial stress-induced behavioral emotionality. Forced expression of SST precursor protein (preproSST), 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 is a SST+ neuron-intrinsic vulnerability factor under conditions of sustained or over-activated UPR in the ER, hence negatively impacting SST+ neuron functions.Competing Interest StatementThe authors have declared no competing interest.