Grant: Project Grant

Somatostatin-positive (SST+) neurons play critical roles in neurotransmission and behaviours related to emotion and cognition. SST+ neuron dysfunctions are reported in diverse brain disorders, including depression, schizophrenia and Alzheimer's disease; however, the molecular origin of SST+ neuron vulnerability remains unknown. Previous studies in postmortem brains in depression and rodent models revealed a dysfunction within SST+ neurons of a housekeeping mechanism, the unfolded protein response (UPR), resulting in increased cellular stress called the endoplasmic reticulum (ER) stress. Importantly, pharmacological or genetic suppression of ER stress in a rodent model normalized the psychosocial stress-induced behavioural emotionality, suggesting that elevated ER stress may serve as a pathophysiological mechanism underlying SST+ neuron vulnerability in depression. We began investigating the origin of SST+ neuron-specific vulnerability with a focus on the SST precursor protein (preproSST), a polypeptide produced by SST+ neurons that undergoes a series of intracellular processing to become the secretable mature SST protein. We found that upregulating preproSST expression, a condition mimicking early proteomic changes induced by psychosocial stress and depression, was sufficient to induce ER stress in SST+ neurons, whereas expressing a mature form of SST or the processing-incompetent mutant of preproSST caused no apparent sign of elevated ER stress. Here we hypothesize that increased ER processing of preproSST induces selective SST+ cell vulnerability, causing elevated emotionality and cognitive deficits. In analogy to other illnesses (i.e. diabetes) where excess ER processing of endogenous proteins (i.e. insulin) causes ER stress and cell dysfunction, this proposal expands the scope of SST+ neuron-selective proteinopathy as a universal pathophysiologic mechanism toward various psychiatric and stress-related brain disorders.