Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular origin of somatostatin-positive neuron vulnerability

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Epelbaum J, Guillou J-L, Gastambide F, Hoyer D, Duron E, Viollet C. Somatostatin, Alzheimer’s disease and cognition: an old story coming of age? Prog Neurobiol. 2009;89:153–61.

    Article  CAS  PubMed  Google Scholar 

  2. Hendry SH, Jones EG, Emson PC. Morphology, distribution, and synaptic relations of somatostatin- and neuropeptide Y-immunoreactive neurons in rat and monkey neocortex. J Neurosci. 1984;4:2497–517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Melchitzky DS, Lewis DA. Dendritic-targeting GABA neurons in monkey prefrontal cortex: comparison of somatostatin- and calretinin-immunoreactive axon terminals. Synapse. 2008;62:456–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu X, Roby KD, Callaway EM. Immunochemical characterization of inhibitory mouse cortical neurons: three chemically distinct classes of inhibitory cells. J Comp Neurol. 2010;518:389–404.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Soumier A, Sibille E. Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice. Neuropsychopharmacology. 2014;39:2252–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lin L, Sibille E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry. 2015;20:377–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fee C, Prevot TD, Misquitta K, Knutson DE, Li G, Mondal P, et al. Behavioral deficits induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation. Int J Neuropsychopharmacol. 2021; pyab002.

  8. Martel G, Dutar P, Epelbaum J, Viollet C. Somatostatinergic systems: an update on brain functions in normal and pathological aging. Front Endocrinol. 2012;3:154.

    Article  Google Scholar 

  9. Fee C, Banasr M, Sibille E. Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: cortical microcircuit and therapeutic perspectives. Biol Psychiatry. 2017;82:549–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prévot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. 2021;26:151–67.

    Article  PubMed  Google Scholar 

  11. Willner P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol Stress. 2016;6:78–93.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tripp A, Kota RS, Lewis DA, Sibille E. Reduced somatostatin in subgenual anterior cingulate cortex in major depression. Neurobiol Dis. 2011;42:116–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guilloux JP, Douillard-Guilloux G, Kota R, Wang X, Gardier AM, Martinowich K, et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry. 2012;17:1130–42.

    Article  CAS  PubMed  Google Scholar 

  14. Girgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes. Transl Psychiatry. 2019;9:292.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ron D, Harding HP. Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol. 2012;4:a013177.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Metcalf MG, Higuchi-Sanabria R, Garcia G, Tsui CK, Dillin A. Beyond the cell factory: Homeostatic regulation of and by the UPRER. Sci Adv. 2020;6:eabb9614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gonen N, Sabath N, Burge CB, Shalgi R. Widespread PERK-dependent repression of ER targets in response to ER stress. Sci Rep. 2019;9:4330.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gerakis Y, Hetz C. Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease. FEBS J. 2018;285:995–1011.

    Article  CAS  PubMed  Google Scholar 

  19. Rozpedek W, Markiewicz L, Diehl JA, Pytel D, Majsterek I. Unfolded protein response and PERK kinase as a new therapeutic target in the pathogenesis of Alzheimer’s disease. Curr Med Chem. 2015;22:3169–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017;13:477–91.

    Article  CAS  PubMed  Google Scholar 

  21. Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, Liu M, Arvan P. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann NY Acad Sci. 2018;1418:5–19.

    Article  CAS  PubMed  Google Scholar 

  22. Negro-Vilar A, Saavedra JM. Changes in brain somatostatin and vasopressin levels after stress in spontaneously hypertensive and Wistar-Kyoto rats. Brain Res Bull. 1980;5:353–8.

    Article  CAS  PubMed  Google Scholar 

  23. Arancibia S, Epelbaum J, Boyer R, Assenmacher I. In vivo release of somatostatin from rat median eminence after local K+ infusion or delivery of nociceptive stress. Neurosci Lett. 1984;50:97–102.

    Article  CAS  PubMed  Google Scholar 

  24. Arancibia S, Rage F, Grauges P, Gomez F, Tapia-Arancibia L, Armario A. Rapid modifications of somatostatin neuron activity in the periventricular nucleus after acute stress. Exp Brain Res. 2000;134:261–7.

    Article  CAS  PubMed  Google Scholar 

  25. Chen XQ, Du JZ. Increased somatostatin mRNA expression in periventricular nucleus of rat hypothalamus during hypoxia. Regul Pept. 2002;105:197–201.

    Article  CAS  PubMed  Google Scholar 

  26. Priego T, Ibanez De Caceres I, Martin AI, Villanua MA, Lopez-Calderon A. Endotoxin administration increases hypothalamic somatostatin mRNA through nitric oxide release. Regul Pept. 2005;124:113–8.

    Article  CAS  PubMed  Google Scholar 

  27. Polkowska J, Wankowska M. Effects of maternal deprivation on the somatotrophic axis and neuropeptide Y in the hypothalamus and pituitary in female lambs. The histomorphometric study. Folia Histochem Cytobiol. 2010;48:299–305.

    Article  PubMed  Google Scholar 

  28. Prévôt TD, Gastambide F, Viollet C, Henkous N, Martel G, Epelbaum J, Béracochéa D, Guillou J-L. Roles of hippocampal somatostatin receptor subtypes in stress response and emotionality. Neuropsychopharmacology. 2017;42:1647–56.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Goodman RH, Aron DC, Roos BA. Rat pre-prosomatostatin. Struct Process microsomal Membr J Biol Chem. 1983;258:5570–3.

    CAS  Google Scholar 

  30. Newton DF, Oh H, Shukla R, Misquitta K, Fee C, Banasr M, et al. Chronic stress induces coordinated cortical microcircuit cell-type transcriptomic changes consistent with altered information processing. Biol Psychiatry. 2021; https://doi.org/10.1101/2020.08.18.249995.

  31. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van Waarde-Verhagen M, Kampinga HH. Measurement of chaperone-mediated effects on polyglutamine protein aggregation by the filter trap assay. Methods Mol Biol. 2018;1709:59–74.

    Article  PubMed  Google Scholar 

  33. Nucifora LG, MacDonald ML, Lee BJ, Peters ME, Norris AL, Orsburn BC, et al. Increased protein insolubility in brains from a subset of patients with schizophrenia. Am J Psychiatry. 2019;176:730–43.

    Article  PubMed  Google Scholar 

  34. Hui KK, Takashima N, Watanabe A, Chater TE, Matsukawa H, Nekooki-Machida Y, Nilsson P, Endo R, Goda Y, Saido TC, Yoshikawa T, Tanaka M. GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior. Sci Adv. 2019;5:eaau8237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guilloux JP, Seney M, Edgar N, Sibille E. Integrated behavioral Z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J Neurosci Methods. 2011;197:21–31.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Seney ML, Huo Z, Cahill K, French L, Puralewski R, Zhang J, Logan RW, Tseng G, Lewis DA, Sibille E. Opposite molecular signatures of depression in men and women. Biol Psychiatry. 2018;84:18–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Riekkinen PJ, Pitkänen A. Somatostatin and epilepsy. Metabolism. 1990;39:112–5.

    Article  CAS  PubMed  Google Scholar 

  38. Solarski M, Wang H, Wille H, Schmitt-Ulms G. Somatostatin in Alzheimer’s disease: a new role for an old player. Prion. 2018;12:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K, Rissman RA, et al. Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science. 2009;325:328–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bradshaw NJ, Korth C. Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness. Mol Psychiatry. 2019;24:936–51.

    Article  CAS  PubMed  Google Scholar 

  41. Sumitomo A, Yukitake H, Hirai K, Horike K, Ueta K, Chung Y, et al. Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. Hum Mol Genet. 2018;27:3165–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bown C, Wang JF, MacQueen G, Young LT. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide. Neuropsychopharmacology. 2000;22:327–32.

    Article  CAS  PubMed  Google Scholar 

  43. Wang H, Muiznieks LD, Ghosh P, Williams D, Solarski M, Fang A, Ruiz-Riquelme A, Pomès R, Watts JC, Chakrabartty A, Wille H, Sharpe S, Schmitt-Ulms G. Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers. Elife. 2017;6:e28401. pii

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sharma V, Sood R, Khlaifia A, Eslamizade MJ, Hung TY, Lou D, et al. eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature. 2020;586:412–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu M, Sun J, Cui J, Chen W, Guo H, Barbetti F, Arvan P. INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol Asp Med. 2015;42:3–18.

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Toshifumi Tomoda or Etienne Sibille.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01463-4

Search

Quick links