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Molecular origin of somatostatin-positive neuron vulnerability

Molecular Psychiatry volume 27, pages 2304–2314 (2022)Cite this article

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Abstract

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.

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Fig. 1: Gene set enrichment analysis of ER stress/UPR-related pathways expressed in neurons of cortical circuitry in UCMS mice.
Fig. 2: ER stress in SST+ neurons induced by UCMS.
Fig. 3: Genetic suppression of ER stress in SST+ neurons ameliorates UCMS-induced behavioral emotionality.
Fig. 4: SST+ neuron-specific ER stress induced by preproSST.
Fig. 5: ER stress-dependent increase in insoluble preproSST peptides in PFC during UCMS.

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Acknowledgements

The authors thank Mohan Pabba, Rammohan Shukla, Mounira Banasr, Thomas Prevot, and Hyunjung Oh for comments or discussion. This work was supported by grants from the Canadian Institute of Health Research (CIHR #153175 to ES), National Alliance for Research on Schizophrenia and Depression (NARSAD award #25637 to ES), the National Institutes of Health (MH-093723 to ES), Campbell Family Mental Health Research Institute (to ES).

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Authors and Affiliations

  1. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, M5T 1R8, Canada

    Toshifumi Tomoda, Akiko Sumitomo, Dwight Newton & Etienne Sibille

  2. Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada

    Etienne Sibille

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5T 1R8, Canada

    Etienne Sibille

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  1. Toshifumi Tomoda
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TT and ES conceived the study and designed the experiments; TT and AS acquired and analyzed data; DN analyzed gene expression profiles; TT and ES wrote and edited the manuscript.

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Correspondence to Toshifumi Tomoda or Etienne Sibille.

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Tomoda, T., Sumitomo, A., Newton, D. et al. Molecular origin of somatostatin-positive neuron vulnerability. Mol Psychiatry 27, 2304–2314 (2022). https://doi.org/10.1038/s41380-022-01463-4

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