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Somatostatin, neuronal vulnerability and behavioral emotionality

Abstract

Somatostatin (SST) deficits are common pathological features in depression and other neurological disorders with mood disturbances, but little is known about the contribution of SST deficits to mood symptoms or causes of these deficits. Here we show that mice lacking SST (SstKO) exhibit elevated behavioral emotionality, high basal plasma corticosterone and reduced gene expression of Bdnf, Cortistatin and Gad67, together recapitulating behavioral, neuroendocrine and molecular features of human depression. Studies in SstKO and heterozygous (SstHZ) mice show that elevated corticosterone is not sufficient to reproduce the behavioral phenotype, suggesting a putative role for Sst cell-specific molecular changes. Using laser capture microdissection, we show that cortical SST-positive interneurons display significantly greater transcriptome deregulations after chronic stress compared with pyramidal neurons. Protein translation through eukaryotic initiation factor 2 (EIF2) signaling, a pathway previously implicated in neurodegenerative diseases, was most affected and suppressed in stress-exposed SST neurons. We then show that activating EIF2 signaling through EIF2 kinase inhibition mitigated stress-induced behavioral emotionality in mice. Taken together, our data suggest that (1) low SST has a causal role in mood-related phenotypes, (2) deregulated EIF2-mediated protein translation may represent a mechanism for vulnerability of SST neurons and (3) that global EIF2 signaling has antidepressant/anxiolytic potential.

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Acknowledgements

We thank Chien-Wei Lin and Ying Ding for assistance with the microarray data preprocessing, Ye Chen for assistance with behavioral testing and Beverly French for comments on the manuscript. This work was supported by grants from National Institute of Mental Health (NIMH-MH093723, MH084060 and MH077159).

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Lin, L., Sibille, E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry 20, 377–387 (2015). https://doi.org/10.1038/mp.2014.184

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