Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

Abstract

Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders.

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

“…Specifically, we found that SST + interneurons were present at various levels of maturity at D54. SST cell death has been observed in mood disorders and dysfunctional SST interneurons have recently been shown to exacerbate cortical excitotoxicity in neurodegenerative disorders (Lin and Sibille, 2013;Zhang et al, 2016). Our analysis determined that several genes important for migration, synaptogenesis, axon outgrowth and ion channel function were differentially expressed by more mature interneurons.…”

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease

“…More advanced fixation techniques [43] Several clinical and experimental studies indicate that the SST system is also implicated in stress, anxiety and depression [64], and there is now direct evidence that, in fact, the receptor involved is SSTR2 [32,33,118]. Notably, depression is a leading neuropsychiatric complication in Alzheimer's disease [94], and an association with chronic life stress and laterlife cognitive dysfunction has been proposed [46].…”

“…SST regulates the metabolism of Aβ through increasing neprylisin activity [90]. SST deficits were also detected in major depressive-and bipolar disorders [64]. Moreover, SSTR2/SSTR3 modulation of monoamine systems may induce antidepressant effects in rats [32,33].…”

The Hypothalamus in Alzheimer’s Disease

“…In the field of clinical investigation was noticed that substance P and hypocretin (orexin), which plays an important role in sleep-wake cycle and food intake, were elevated in the CSF in a substantial number of AD patients in comparison with normal controls [13,14]. Somatostatin (SST) is consistently reduced in the hypothalamus and neocortical areas in AD [15,16], correlating with cognitive decline, although it is well documented that the SST system is also implicated in stress, anxiety and depression [17].…”