Dr. Tomoda and colleagues just published a new research article in the journal Molecular Psychiatry, reporting their findings on the molecular origins of somatostatin neuron vulnerability across disorders.

SST-positive interneurons are the major inhibitory neuron subtype playing important roles in neurotransmission and behaviors related to emotion and cognition. Dysfunction of this neuron subtype is reported across many brain disorders, including depression and neurological disorders (such as Alzheimer’s disease), and believed to cause low mood associated with these brain disorders.

In this paper, using the chronic psychisocial stress model in mice, we show selective dysfunction of a housekeeping cellular mechanism, the unfolded protein response (UPR) of the endoplasmic reticulum (ER), and consequent overactivated cellular stress called the ER stress within SST+ neurons. In further search for the molecular origin of SST+ neuron vulnerability, we focused on preproSST, an SST+ neuron-intrinsic neuropeptide that undergoes step-wise intracellular processing (i.e. ER insertion, proteolytic cleavage, vesicle packaging, secretion) to become the bioactive, mature SST peptide. We found that upregulating preproSST expression, a condition mimicking early

proteomic changes induced by psychosocial stress, is sufficient to induce ER stress in SST+ neurons and to cause elevated behavioral emotionality, whereas expressing a mature form of SST or the processing-incompetent SST mutant failed to do so. Moreover, SST proteins showed a sign of proteinophathy (i.e. aggregate-prone property) due to elevated ER stress in mice exposed to chronic psychosocial stress. Therefore, the SST peptide itself is an intrinsic pathophysiology-inducing factor when excess or sustained demand for its ER processing negatively impacts SST+ neurons.

In analogy to other illnesses (i.e. diabetes) where excess ER processing of endogenous proteins (i.e. insulin) causes ER stress and cell dysfunction, our study expands the scope of SST+ neuron-selective proteinopathy as a universal pathophysiologic mechanism toward various psychiatric and stress-related brain disorders.