New funding!Genetic and non-genetic mechanisms for somatostatin neuron vulnerability in stress-related brain disorders

We are thrilled to announce that Dr. Tomoda is the recipient of a CIHR Project Grant, for the period of 2022-2026. This project will investigate the molecular origin of somatostatin-positive interneuron vulnerability in the corticolimbic circuitry pertinent to the susceptibility to develop behavioural emotionality related to the pathophysiology of mood disorders.

Lay Abstract:

Somatostatin-positive (SST+) neurons, a major inhibitory neuron subtype, 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 in rodent models revealed a dysfunction in SST+ neurons of a housekeeping mechanism, the unfolded protein response (UPR) machinery, and consequent increase in 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 recently 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.

Based on these lines of evidence, we hypothesize that increased processing of SST induces selective SST+ cell vulnerability. In this proposal we will elucidate the mechanisms by which excessive or aberrant SST processing elicits SST+ neuron-specific UPR dysfunction and elevated ER stress, thereby causing functional outcomes, such as elevated emotionality and cognitive deficits relevant to depression and other stress-related brain disorders.