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. 2015 Mar;20(3):377-87.
doi: 10.1038/mp.2014.184. Epub 2015 Jan 20.

Somatostatin, neuronal vulnerability and behavioral emotionality

L C Lin  1 , E Sibille  2
Affiliations

Somatostatin, neuronal vulnerability and behavioral emotionality

L C Lin et al. Mol Psychiatry. 2015 Mar.

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.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Loss of somatostatin (Sst) leads to high anxious/depressive-like behavior in the novelty suppressed feeding (NSF) test and overall elevated behavioral emotionality
(A) Before and after exposure to unpredictable mild chronic stress (UCMS), SstKO mice display increased latency in the NSF test and elevated overall emotionality Z-score (an integrated result from four related tests; Details in Fig. S1). UCMS induced a typical progressive fur coat degradation, which did not differ between groups (middle). (B) Locomotion, as measured by the total number of arm entries in the elevated plus maze (EPM) or total distance traveled in the open field (OF), and overall locomotion z-scores, did not differ between SstKO and wild-type mice at baseline. (C) After UCMS SstKO displayed reduced locomotion in the OF but not overall differences. (D) Basal corticosterone levels were elevated in SstKO and SstHZ mice. (E) Acute stress-induced corticosterone levels were normal in mice with low SST. (F) No abnormal corticosterone levels were detected in mice with low SST during the recovery period. *p<0.05, **p<0.01, ****p<0.001. Error bars represent the standard error of the mean. (n=12–15 mice per genotype, 6–9 mice per sex).
Figure 2
Figure 2. Transcriptome changes induced by chronic stress reveal a selective vulnerability of Sst neurons, compared to pyramidal neurons
(A) Scheme depicting the use of laser capture microdissection (LCM) to capture individual cell types. Bar represent 20 μm. (B–C) Distributions of stress effects for (B) effect size (Average log2 ratio; Alr; changes > 20%; vertical dashed lines) and (C) significance (p-value; p<0.05; horizontal dashed lines) of all expressed probesets in SST neurons (red lines) and pyramidal neurons (PYR; black lines) were presented as density plots. These probability distributions between SST neurons and pyramidal neurons were significantly different. p-value was calculated by Kolmogorov-Smirnov (K–S) test. (D) qPCR confirms significant down-regulation of Sst and Gad67 transcripts in UCMS-exposed mouse SST neurons.
Figure 3
Figure 3. Attenuation of anxiety/depression-like behaviors in stressed mice after treatment with GSK2606414, an EIF2A-mediated inhibitor of cellular stress response
(A) Experimental design. (B) Anxiety/depressive-like behaviors in the NSF test were increased after UCMS treatment, and GSK2606414 treatment significantly eliminated UCMS effects on behaviors. (C) The same effects of UCMS and GSK2606414 on emotionality were confirmed with emotionality Z-scores. (D–F) No treatments affected overall locomotion, body weight, or post-NSF feeding at home cage. *p<0.05, **p<0.01, ***p<0.005, ****p<0.001. Error bars represent the standard error of the mean (n =8–12/group).
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