Somatostatin, neuronal vulnerability and behavioral emotionality

L C Lin; E Sibille

doi:10.1038/mp.2014.184

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Somatostatin, neuronal vulnerability and behavioral emotionality

Journal article

Open access

Peer reviewed

Somatostatin, neuronal vulnerability and behavioral emotionality

L C Lin and E Sibille

Molecular psychiatry, Vol.20(3), pp.377-387

03/2015

DOI: 10.1038/mp.2014.184

PMCID: PMC4355106

PMID: 25600109

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https://doi.org/10.1038/mp.2014.184View

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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 (Sst(KO)) 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 Sst(KO) and heterozygous (Sst(HZ)) 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.

Adenine - analogs & derivatives

Adenine - pharmacology

Adenine - therapeutic use

Animals

Antidepressive Agents - pharmacology

Antidepressive Agents - therapeutic use

Brain-Derived Neurotrophic Factor - metabolism

Corticosterone - blood

Disease Models, Animal

Eukaryotic Initiation Factor-2 - metabolism

Female

Gene Expression Regulation - drug effects

Gene Expression Regulation - genetics

Glutamate Decarboxylase - metabolism

Green Fluorescent Proteins - genetics

Green Fluorescent Proteins - metabolism

Gyrus Cinguli - pathology

Indoles - pharmacology

Indoles - therapeutic use

Male

Mice

Mice, Inbred C57BL

Mice, Transgenic

Mood Disorders - blood

Mood Disorders - etiology

Mood Disorders - genetics

Mood Disorders - pathology

Neurons - metabolism

Signal Transduction - genetics

Somatostatin - genetics

Somatostatin - metabolism

Stress, Psychological - blood

Stress, Psychological - complications

Stress, Psychological - genetics

Transcriptome - genetics

Details

Title: Subtitle: Somatostatin, neuronal vulnerability and behavioral emotionality
Creators: L C Lin - University of Pittsburgh
E Sibille - Centre for Addiction and Mental Health
Resource Type: Journal article
Publication Details: Molecular psychiatry, Vol.20(3), pp.377-387
DOI: 10.1038/mp.2014.184
PMID: 25600109
PMCID: PMC4355106
NLM abbreviation: Mol Psychiatry
ISSN: 1359-4184
eISSN: 1476-5578
Grant note: R01 MH093723 / NIMH NIH HHS MH084060 / NIMH NIH HHS K02 MH084060 / NIMH NIH HHS R01 MH077159 / NIMH NIH HHS MH093723 / NIMH NIH HHS MH077159 / NIMH NIH HHS
Language: English
Date published: 03/2015
Academic Unit: Neurology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984184143302771

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