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 to 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. Together, our data suggest that (1) low SST plays 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.

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

“…Follow-up investigation in the ACC demonstrated reduced SST expression per cell across all cortical layers (83), suggesting a common origin despite SST cell heterogeneity. A putative causal role for reduced SST cell function is supported by work showing that Sst knockout mice recapitulated several MDD hallmarks, including elevated depressive-/anxiety-like behaviors, increased corticosterone, and reduced expression of brain-derived neurotrophic factor ( Bdnf ) and Gad67 genes, although, these changes were not seen in Sst Hz mice, possibly due to compensatory cellular adaptations (85). Note that SST is co-released with GABA, has pre- and post-synaptic physiological and neuronal roles (See review (86)), and when infused into rodent corticolimbic brain regions, has anxiolytic- and antidepressant-like effects (87–90).…”

“…Mouse models of depression using unpredictable chronic mild stress ( UCMS ) or elevated glucocorticoid exposure recapitulated SST and GABA-related deficits (85). Sex differences have also been implicated, as MDD-related SST reductions are more severe in females (82, 83), who are twice as likely to develop mood disorders (119).…”

“…Cross-sectional postmortem studies demonstrated progressive early reductions of SST in SCZ and MDD (120, 121), and BDNF-dependent genes in MDD (93), suggesting that accelerated brain molecular aging may contribute to SST cell vulnerability (120). Similarly, rodent chronic stress models showed altered SST cell function from disrupted cellular homeostatic mechanisms, including endoplasmic reticulum ( ER ) and mitochondrial-related oxidative stress (85, 118). ER stress is a form of cellular stress implicated in normal aging and neurodegenerative disorders, resulting from allostatic overload or extracellular stimuli impairing ER protein translation, leading to an accumulation of unfolded proteins.…”

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

“…SST interneurons are altered following chronic stress exposure, and dysfunction of these neurons is thought to contribute to depressive symptoms (39,40). Postmortem studies have reported a reduced number of calbindin + (putative SST) interneurons and decreased expression of SST interneuron markers in the PFC (41,42), demonstrating that altered SST/GABA function is associated with depressive symptoms (43).…”

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

“…Altered levels and signaling of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, is frequently reported in depression [1, 2], anxiety disorder [3], normal ageing [4], and neurodegenerative disorders, including Alzheimer’s disease [5], and in multiple brain regions including the prefrontal cortex [6] and anterior cingulate cortex [7]. Recent studies showed that such reductions of GABA levels in the human brain are associated with cognitive impairments in an age-dependent manner [8] and are further worsened during older age [9].…”