REVIEW ARTICLE published: 09 September 2013 doi: 10.3389/fphar.2013.00110 Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

Li-Chun Lin and Etienne Sibille* Department of Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

Edited by: Our knowledge of the pathophysiology of affect dysregulation has progressively increased, Thibault Renoir, Florey Institute of but the pharmacological treatments remain inadequate. Here, we summarize the cur- Neuroscience and Mental Health, Australia rent literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. Reviewed by: Jean-Philippe Guilloux,Université We focus on direct evidence in the human postmortem brain, and review rodent Paris Sud, France genetic and pharmacological studies probing the role of the somatostatin system in Jacques Epelbaum, Université Paris relation to mood. We also briefly go over pharmacological developments targeting the Descartes, France Elif Engin, McLean Hospital/Harvard somatostatin system in peripheral organs and discuss the challenges of targeting the Medical School, USA brain somatostatin system. Finally, the fact that somatostatin deficits are frequently *Correspondence: observed across neurological disorders suggests a selective cellular vulnerability of Etienne Sibille, Department of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes Psychiatry, Center for Neuroscience, are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunc- University of Pittsburgh, Bridgeside Point II, 450 Technology Drive, Suite tion, high inflammatory response, high demand for neurotrophic environment, and 231, Pittsburgh, PA 15219, USA overall aging processes. Together, based on the co-localization of somatostatin with e-mail: [email protected] gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron sub- types, 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. View metadata, citation and similar papers at core.ac.uk brought to you by CORE

Keywords: somatostatin, somatostatin-expressing interneurons, SST, SOM, SRIF, depression, mood disorders, provided by Frontiers - Publisher Connector GABA inhibition

INTRODUCTION This article highlights current findings on the functional roles of Mood disturbances are commonly observed in many neuro- somatostatin in local neuronal circuits, and reviews somatostatin logical disorders. The chronic, recurrent and long duration deficits across neurological disorders, including neuropsychi- of mood disturbances not only place an enormous emotional atric disorders [e.g., major depressive disorder (MDD), bipolar and financial burden on patients, but also on their fami- disorder, schizophrenia], and neurodegenerative disorders (e.g., lies and society. Nearly 10% of all primary care office visits Parkinson’s, Alzheimer’s, and Huntington’s diseases; Table 1). are depression-related (Stafford et al., 2000), but only 30% of This raises interesting questions, including first; whether the patients with mood disturbances achieve remission with ini- somatostatin deficits observed in neurological disorders repre- tial treatment (Trivedi et al., 2006). Somatostatin is a pep- sent common, distinct, or partly overlapping mechanisms of tide expressed in multiple organs. In the brain, somatostatin symptoms across disorders and, second, what may be the causes (also known as somatotrophin release inhibiting factor and and biological mechanisms underlying the selective neuronal vul- often abbreviated as SST, SRIF, or SOM) acts as a modulatory nerability of somatostatin-expressing neurons. In addition, we and inhibitory neuropeptide that is co-localized with gamma- review somatostatin findings associated with affect regulation aminobutyric acid (GABA), and that is involved in regulating at the genetic, cellular, and pharmacological levels in animal multiple aspects of physiological and behavioral stress responses, studies. So far, these findings suggest that somatostatin deficits including inhibition of hypothalamic hormone release, amyg- across different brain systems and diseases may play a central dala central nucleus output, and cortical local circuit integra- role in the affective symptom dimension rather than non-specific tion of sensory input. Research advances over the past three signals in neurological disorders (Figure 1). As somatostatin decades suggest a critical role for somatostatin in the patho- itself is not an ideal drug target, including for antidepres- physiology of mood disorders, and potential new therapeutic sant effect, we suggest that further studies characterizing the strategies. Several recent reviews have summarized the role of the intrinsic properties and biological vulnerabilities of somatostatin- somatostatin system, including in receptor subtypes (Patel, 1999; expressing neurons, may identify novel targets with implications Csaba and Dournaud, 2001), pharmacological developments for understanding the function of local cell circuits and brain (Neggers and van der Lely, 2009), and during normal and patho- regions underlying affective symptoms across several neurological logical aging (Patel, 1999; Viollet et al., 2008; Martel et al., 2012). disorders.

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Table 1 | Low somatostatin in human neurological disorders.

Neurological disorders Brain region Pathological findings Reference

Major depressive disorder CSF Decreased Agren and Lundqvist (1984), Kling et al. (1993), Molchan et al. (1993) Dorsolateral prefrontal cortex Decreased (RNA expression) Sibille et al. (2011) Anterior cingulate cortex Decreased (RNA expression) Tripp et al. (2011), Tripp et al. (2012) Amygdala Decreased (RNA and protein expression) Guilloux et al. (2012) Schizophrenia CSF Decreased Bissette et al. (1986), Reinikainen et al. (1990) Dorsolateral prefrontal cortex Decreased (RNA expression) Morris et al. (2008), Guillozet-Bongaarts et al. (2013) Hippocampus Decreased (neuron number and density) Konradi et al. (2011a) Caudal entorhinal cortex Decreased (neuron number and density) Wang et al. (2011) Parasubiculum Decreased (neuron number and density) Wang et al. (2011) Bipolar disorder Caudal entorhinal cortex Decreased (neuron density) Wang et al. (2011) Parasubiculum Decreased (neuron density) Wang et al. (2011) Hippocampus Decreased (neuron number and RNA expression) Konradi et al. (2011b) Dorsolateral prefrontal cortex Decreased (RNA expression; trend level) Sibille et al. (2011) Alzheimer’s disease CSF Decreased Bissette et al. (1986); Tamminga et al. (1987) Temporal cortex Decreased (immune-reactivity) Rossor et al. (1980); Candy et al. (1985) Frontal cortex Decreased (immune-reactivity) Davies and Terry (1981); Candy et al. (1985) Hippocampus Decreased (gene expression per cell) Dournaud et al. (1994) Parahippocampal cortex Decreased (neuronal density) Dournaud et al. (1994) Parkinson’s disease CSF Decreased Dupont et al. (1982) Frontal cortex Decreased (radioimmune-reactivity) Epelbaum et al. (1988) Others Temporal cortex Decreased (immune-reactivity) Beal et al. (1986)

LOW SOMATOSTATIN IN NEUROPSYCHIATRIC AND dorsolateral prefrontal cortex (dlPFC), subgenual anterior cingu- NEURODEGENERATIVE DISORDERS late cortex (sgACC), and amygdala (Sibille et al., 2011; Tripp et al., MAJOR DEPRESSIVE DISORDER 2011, 2012; Guilloux et al., 2012). In addition, two peptides co- Patients with major depressive disorder (MDD) show decreased localized with somatostatin, neuropeptide Y and cortistatin, are somatostatin levels in the cerebrospinal fluid (CSF; Agren and both significantly down-regulated in MDD patients (Tripp et al., Lundqvist, 1984; Molchan et al., 1991; Kling et al., 1993), and tran- 2011, 2012).These three neuropeptides (somatostatin, neuropep- siently decreased CSF somatostatin which normalize with recovery tide Y, and cortistatin) are markers of GABAergic neurons that in MDD (Rubinow et al., 1985; Post et al., 1988). Evidence for low specifically target the dendritic compartment of pyramidal cells levels of CSF somatostatin was found to correlate significantly (de Lecea et al., 1997; Viollet et al., 2008), and that are essential with elevated urinary cortisol in MDD patients (Molchan et al., in gating incoming sensory information (Figure 1). Other types 1993). This is consistent with the altered hypothalamic-pituitary- of GABAergic cell markers, such as parvalbumin and cholecys- adrenal (HPA) axis function described in some depressed patients tokinin, are mostly not affected by MDD (although see Tripp et al., (Holsboer, 2000). The route and characterization, however, from 2012). Interestingly, these somatostatin deficits were systematically CSF somatostatin to MDD pathophysiology is not direct, poten- more robust in female subjects across cohorts and regions (Sibille tially due to a paucity of information on factors regulating CSF et al., 2011; Tripp et al., 2011, 2012; Guilloux et al., 2012), consis- somatostatin, and to inconclusive somatostatin/HPA axis studies tent with the female heightened vulnerability to develop MDD, in MDD patients. Hence, despite these early findings, interest in and suggesting that low somatostatin may represent a molec- somatostatin in mood disorders has declined over time. ular correlate of sexual dimorphism in vulnerability to affect Human post-mortem studies from our group have described dysregulation. Notably, these findings are also consistent with region-specific somatostatin deficits in MDD patients, includ- earlier postmortem studies showing reduced calbindin-positive ing a down-regulation of somatostatin gene expression in the cell numbers in MDD (Rajkowska et al., 2007; Maciag et al.,

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FIGURE 1 | Schematic of somatostatin signaling, pathological regulators expressing interneurons are key conduits for regulating incoming information and biological functions relevant to affect regulation. Somatostatin and pyramidal cell function. In contrast, other GABA neurons subtypes pathway activity is responsive to (left panel), and regulates (right panel), targeting the perisomatic pyramidal cell compartment are mostly not affected several biological events, and molecular and cellular properties that have in major depression. NPY, neuropeptide Y; PYR, pyramidal neuron; PV, been linked to mood disturbances. Somatostatin and somatostatin- parvalbumin.

2010), as somatostatin is mostly expressed in a subgroup of 2011b). In addition, patients with bipolar disorder show elevated calbindin-positive cells (reviewed in Viollet et al., 2008). Converg- CSF somatostatin during manic states (Sharma et al., 1995). ing evidence from down-regulation of somatostatin co-localized GABA markers in MDD across multiple human post-mortem NEURODEGENERATIVE DISORDERS studies suggests that this particular GABA subpopulation in the Alzheimer’s disease is a neurodegenerative disease with neu- forebrain is selectively vulnerable, among other subtypes of GABA ropsychiatric symptoms (Bungener et al., 1996). Decreased CSF neurons. Furthermore, these local cell circuit-based findings intro- somatostatin (Bissette et al., 1986; Tamminga et al., 1987) and duce a new role for somatostatin in depression, which is distinct decreased somatostatin immune-reactivity across cortical and from its previously investigated role in the regulation of the HPA subcortical regions is reported in subjects with Alzheimer’s dis- axis (Rubinow et al., 1983; Molchan et al., 1993; Weckbecker et al. ease, including temporal cortex, frontal cortex, and hippocampus 2003). (Davies et al., 1980; Rossor et al., 1980; Davies and Terry, 1981; Candy et al., 1985; Dournaud et al., 1994). Depression is a com- OTHER NEUROPSYCHIATRIC DISORDERS mon comorbid symptom in Parkinson’s disease and predicts Schizophrenia is a neuropsychiatric disorder characterized by greater disability at any assessment point (Aarsland et al., 1999). positive (e.g., hallucination), negative symptoms (e.g., emo- Decreased CSF somatostatin, decreased somatostatin immuno- tional blunting, apathy) and cognitive symptoms. Somatostatin reactivity, and binding sites are also observed in the temporal deficits in schizophrenia are demonstrated by a reduction of cortex and frontal cortex of patients with Parkinson’s disease (Beal CSF somatostatin (Bissette et al., 1986; Reinikainen et al., 1990), et al., 1986; Epelbaum et al., 1988). Notably, reduced CSF somato- decreased somatostatin gene expression in the dlPFC (Mor- statin in Parkinson’s disease appears to be irreversibly present at ris et al., 2008; Guillozet-Bongaarts et al., 2013), and decreased the onset of symptoms (Dupont et al., 1982). number and density of somatostatin-expressing neurons in the hippocampus (Konradi et al., 2011a), caudal entorhinal cortex REDUCED SOMATOSTATIN AND LOW MOOD? and parasubiculum (Wang et al., 2011). Changes in somatostatin The evidence outlined in this review provides only a glimpse of the are also identified in bipolar disorder, which is clinically char- potential full range of somatostatin deficits across neurological dis- acterized by fluctuating mood. Studies in subjects with bipolar orders, as multiple other brain regions and disease categories await disorder indicate decreases in somatostatin cellular density in the further characterization (Table 1). Taken together, the cumula- caudal entorhinal cortex and parasubiculum (Wang et al., 2011), tive evidence demonstrates that somatostatin deficits are common number of somatostatin-expressing neurons in the hippocampus neurochemical and molecular features in individuals with neuro- (Konradi et al., 2011b), somatostatin gene expression in the dlPFC logical disorders, regardless of their categorical diagnosis. While (trend level; Sibille et al., 2011) and hippocampus (Konradi et al., somatostatin studies of cell number and gene expression in human

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postmortem brains suggest a specific alteration of somatostatin- activation of inhibitory G protein (Gi) and the following inhi- positive neurons across neurological disorders, it is possible bition of adenylyl cyclase, leading to reduction of cAMP levels, that changes and dys-synchronization of additional components activation of phosphotyrosine phosphatases, and modulation of of local neuronal circuits contribute to a common symptom mitogen-activated protein kinases and phospholipase C (Koch and dimension, which we speculate includes low affect and mood dys- Schonbrunn, 1984; Koch et al., 1988). regulation. Hence, this review is not comprehensive, but rather, Sst1−5 present different patterns of coexpression in the brain highlights the recent findings in brain somatostatin signaling and (Kluxen et al., 1992; Moller et al., 2003; reviewed in Martel et al., the potential role of somatostatin deficits in affect dysregula- 2012). Sst1 is found in retina, basal ganglia and hypothalamus, tion for integrating categorical models of mood symptoms into Sst2 is highly abundant in several telencephalic structures (neo- a dimensional model across neurological disorders. cortex, hippocampus, and amygdala), Sst3 immunoreactivity has only been described in neuronal cilia (Schulz et al., 2000), Sst4 SOMATOSTATIN: GENES, NEURONS AND PHARMACOLOGY is expressed in olfactory bulb, cerebral cortex and CA1 region of SOMATOSTATIN SIGNALING the hippocampus (Schreff et al., 2000), and expression of Sst5 has Somatostatin is a modulatory neuropeptide that synergizes with been detected in cerebral cortex, hippocampus, amygdala, pre- GABA-mediated inhibition, and that specifically targets the optic area, and hypothalamus (Stroh et al., 1999; Strowski et al., distal dendritic compartment of pyramidal neurons in corti- 2003; Olias et al., 2004). Interestingly, when co-expressed in the cal local circuits (Kawaguchi and Kubota, 1997; Gentet et al., same cells, Sst5 influences Sst2 internalization and trafficking and 2012). Somatostatin inhibits release of numerous hormones from modulates cellular desensitization to the effects of somatostatin-14 the hypothalamus, including corticotrophin releasing hormone (Sharif et al., 2007), suggesting that the precise actions of somato- (CRH;Wanget al.,1987; Patel,1999). The somatostatin gene prod- statin depend on the specific interaction of the Sst1−5 receptors uct is composed of 14 or 28 amino-acid residues. Both forms of expressed locally in each brain region. somatostatin, somatostatin-14 and somatostatin-28, are generated by tissue-specific post-translational processing of the 116 amino- GENETIC POLYMORPHISMS IN THE SOMATOSTATIN SYSTEM acid pre-pro-somatostatin peptide (Warren and Shields, 1984; The relatively high degree of amino acid conservation across Tostivint et al.,2008). Somatostatin-14 is predominantly produced species indicates that somatostatin-related genes have been in the central nervous system (CNS) but also in many peripheral highly constrained during evolution (Patel, 1999; Olias et al., organs (Epelbaum, 1986). Somatostatin-28 is mainly synthesized 2004). Accordingly, there are currently very few reports linking along the gastrointestinal tract (Fitz-Patrick and Patel, 1981). The somatostatin gene polymorphisms with neurological disorders. 5-upstream sequence of the somatostatin gene contains cyclic- A primate-specific single nucleotide polymorphism (SNP) in AMP response element (CRE; Montminy et al., 1986), making the human somatostatin gene [C/T polymorphism (rs4988514)] its expression activity-dependent. Thus, somatostatin expression is associated with increased risk in Alzheimer’s disease pro- is preferentially altered by various stressors, such as seizures gression and additive effect with the APOE epsilon4 allele (Vezzani and Hoyer, 1999; Tallent and Qiu, 2008) and electri- (Vepsalainen et al., 2007; Xue et al., 2009), although this was not cal foot shock (Ponomarev et al., 2010). Moreover, mice with confirmed in larger genome-wide association studies (GWAS) conditional homozygous and constitutive heterozygous brain- (Hollingworth et al., 2011; Guerreiro et al., 2013). Leu48Met and derived neurotrophic factor (Bdnf) knockout or disruption of Pro335Leu SNPs in the SST5 gene are of potential significance to exon IV-expressing Bdnf transcripts show decreased somatostatin patients with bipolar disorder (Nyegaard et al., 2002), but no asso- gene expression (Glorioso et al., 2006; Martinowich et al., 2011; ciations of SST5 SNPs are found in patients with autism (Lauritsen Guilloux et al., 2012), demonstrating that somatostatin expression et al., 2003). The paucity of associations with somatostatin gene depends on Bdnf signaling. However, the molecular mechanisms variants is surprising and may reflect either strong negative selec- by which this neurotrophic factor controls somatostatin and tion against genetic variations in this gene, or alternatively, dilution somatostatin-expressing neurons are still unknown. of signal due to heterogeneity of DSM-IV-based cohorts in genetic Somatostatin, cortistatin and their receptors are closely inter- association studies. So, dimensional phenotypes, as defined by twined systems (de Lecea et al., 1996, 1997; reviewed in Spier and clusters of mood symptoms, which are closer to gene functions de Lecea, 2000; de Lecea, 2008). Sharing high structural homology may have implications for future genetic studies of somatostatin with somatostatin, cortistatin binds to all somatostatin receptor and other genes. subtypes and is known to be regulated by exon IV-expressing Bdnf transcripts (Martinowich et al., 2011). However, distinct SOMATOSTATIN-EXPRESSING NEURONS: DIVERSITY AND ROLES from somatostatin, cortistatin binds to additional receptors (e.g., Gamma-aminobutyric acid (GABA) neurons are a diverse group growth hormone secretagogue receptor 1a and Mas-related gene of inhibitory cells which co-release neuropeptides in order to sup- X2 receptor) (Robas et al., 2003; Siehler et al., 2008) and has port a fine-tuning of neuronal signaling and architecture. The local different physiological properties (e.g., activation of cation selec- inhibitory circuits provide spatiotemporal control of information tive currents not responsive to somatostatin; Spier and de Lecea, processing through at least 20 subtypes of cortical GABA neurons, 2000), suggesting that somatostatin and cortistatin may both con- which are based on their expression of different calcium binding tribute to affect regulation in an integrated, yet differential mode. proteins and neuropeptides, localization, targeting, and differ- The intracellular pathway of somatostatin signaling coupled to ential electrophysiological properties. Recent detailed reviews on all five somatostatin receptors subtypes (Sst1−5) is through the GABA neuron subpopulations have been published (Csaba and

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Dournaud, 2001; Di Cristo et al., 2004; Markram et al., 2004; Tan demonstrated that SstKO mice are healthy, fertile, and show no et al., 2008; Fishell and Rudy, 2011; Gentet et al., 2012; DeFelipe overt behavioral phenotypes, including anxiety-like behavior in et al., 2013; Le Magueresse and Monyer, 2013). Approximately 20– the open-field and fear conditioning tests. Notably, SstKO mice 30% of GABA neurons in the mouse somatosensory cortex express display high basal plasma levels of corticosterone and growth hor- somatostatin (Lee et al., 2010; Rudy et al., 2011), and 40–50% of mone (Zeyda et al., 2001), confirming a somatostatin-mediated GABA neurons contain parvalbumin without overlapping with inhibition of HPA axis function. Similarly, mice lacking indi- somatostatin in the frontal cortex, primary somatosensory cortex vidual Sst1−5 receptors have been tested in numerous biological and visual cortex of mouse (Gonchar et al., 2007; Xu et al., 2010) fields. Of these, Sst2 emerged as the primary receptor of inter- KO and the visual cortex of rat (Gonchar and Burkhalter, 1997). est (Zeyda and Hochgeschwender, 2008), and Sst2 mice display Recent reports focusing on the patterns of cortical neu- increased anxiety-like behavior in the elevated plus maze and open ronal connectivity show that somatostatin-expressing interneu- field, increased immobility in the forced swim test, decreased loco- rons mediate the firing of pyramidal neurons with a fine level motion coupled with an increase of pituitary adrenocorticotropic of specificity among cortical layers. Integrating optogenetic and hormone release instead of growth hormone (Viollet et al., 2000). KO electrophysiology approaches, mouse somatostatin-expressing In line with the observed changes in Sst2 mice, acute predator interneurons in layer 2/3 of the somatosensory cortex provide stress in rats led to up-regulated Sst2 gene expression in the amyg- a tonic inhibition to the distal dendrites of excitatory pyramidal dala and cingulate cortex, shown correlated with Fos expression neurons by sharpening selectivity during periods of quiet wake- in the amygdala (Nanda et al., 2008). As the product of a different fulness, which may contribute to synchronized firing in cortical gene, cortistatin shares a high structural and functional similar- networks and sensorimotor integration (Gentet et al.,2012). Inter- ity with somatostatin-14 (de Lecea et al., 1996, 1997). Notably, estingly, in mouse somatosensory cortex, somatostatin-expressing compared with the weak inhibitory effects of somatostatin on interneurons show a spatially precise connectivity with pyrami- the basal release of CRH from rat hypothalamus and hippocam- dal neurons through direct targeting in layers 2/3 or indirectly pus, cortistatin exhibits strong inhibition of the expression and through inhibition of local parvalbumin interneurons in layer 4 release of basal CRH (Tringali et al., 2012). These findings sug- (Xu et al., 2013). Moreover, in layers 2/3 of the mouse prefrontal gest that Sst2 may regulate affective phenotypes and HPA axis cortex, somatostatin-expressing interneurons compartmentalizes responses both through somatostatin and cortistatin. Given the inhibitions of calcium signaling to spine heads, not shafts, sug- limitations of human studies, SstKO mice provide an opportunity gesting that dendrite-targeting inhibition through somatostatin- to explore the causal role of somatostatin in affect dysregulation expressing interneurons may contribute to downstream cellular and the underlying neural mechanisms. Such insights, however, processes such as synaptic plasticity (Chiu et al., 2013). In mouse will require systematic behavioral characterization with fine spa- visual cortex, somatostatin-expressing interneurons are found to tial and temporal resolution by including female cohorts and mediate response levels of specific subsets of pyramidal neu- region-specific manipulation at different developmental stages. rons whereas parvalbumin-expressing neurons alter response gain Based on the published studies to date, it is still unclear whether (Wilson et al., 2012). Parvalbumin-expressing neurons receive these mutants recapitulate behavioral features of mood disorders. excitatory input from the thalamus and make strong synapses on Knowing the effects of somatostatin signaling on neuroendocrine the soma and axons of their target cells (Kawaguchi and Kubota, regulation, future studies need to assess the molecular and cellu- 1997) to control spike timing of the output neurons. In contrast, lar systems that somatostatin mutations converge upon, and where somatostatin-expressing neurons mostly do not receive input from the exact neural circuits are affected. Moreover, combining genetic thalamus (Beierlein et al., 2003; Cruikshank et al., 2010) and are and environmental factors in animal models is critical to enhance instead activated through feed-forward mechanisms by activated the accuracy of disease modeling and translational efforts. For pyramidal neurons. Somatostatin-expressing interneurons prefer- example, acute or chronic exposure to stress or to stress hormones entially target distal dendrites of pyramidal neurons in layer 2/3 to may capture how such etiological factors determine the vulnera- modulate the processing of incoming sensory information before bility to external insults, in contrast to baseline behavioral testing. it is integrated at the soma level (Di Cristo et al., 2004; Markram In addition, mood disorder-related sex differences are observed et al., 2004; Tan et al., 2008; Murayama et al., 2009; Xu et al., 2013). in community-based epidemiological studies, where the factor of Hence, the distinct GABAergic and prototypical inhibitory pop- seeking treatment is removed (Kornstein et al., 2000; Festinger ulations, expressing either parvalbumin or somatostatin, shape et al., 2008; Leach et al., 2008) and findings of low somatostatin in the spatiotemporal control of multiple post-synaptic potentials in the amygdala appear more robust in postmortem studies of female cortical local circuits, and provide a framework to investigate the MDD subjects (Tripp et al., 2012), suggesting that gender/sex may role of inhibitory circuits in physiology and pathology. represent a biological predisposing factor, or at least a moderating factor, in the intrinsic vulnerability of the somatostatin system. GENETIC APPROACHES TO INVESTIGATE THE SOMATOSTATIN SYSTEM Although many mood disorders emerge during adolescence Mice mutant for somatostatin were created by deleting the cod- (Paus et al., 2008), behavioral abnormalities including affect dys- ing region of the pre-pro-somatostatin (the last ten codons of regulation are often heritable and apparent before diagnostic crite- the first exon; Zeyda et al., 2001). Somatostatin knockout (KO; riaaremet(McGuffin et al., 2003; Geller et al., 2006). It is unclear SstKO ) mice show intact motor coordination and motor learning, when somatostatin deficits occur and potentially begin to con- but have a significant impairment in motor learning as demands tribute to the formation of affective symptoms. Tracking somato- of motor coordination are increased. Overall, a detailed analysis statin system using new anatomic techniques with refined cellular

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definition, from Brainbow (Livet et al., 2007) to CLARITY (Chung (Yeung et al., 2011). Moreover, anxiolytic effects in the elevated et al., 2013) and SeeDB (Ke et al., 2013), across different develop- plus-maze test are described after intra-cerebroventricular infu- mental stages may help identify age-dependent neural architecture sions of a selective Sst2 receptor agonist, but not after infusions of and disease mechanisms related to somatostatin function. the other four receptor agonists; antidepressant-like effects in the forced swim test are observed following infusions of either Sst2 or SOMATOSTATIN ANALOG DEVELOPMENT AND PHARMACOLOGICAL Sst3 agonists (Engin and Treit, 2009). Another agent to enhance STUDIES somatostatin functioning, SRA880 (an antagonist of auto-receptor As native somatostatin peptides have a very short half-life time Sst1), synergizes with imipramine in causing antidepressant-like (approximate 1–3 min; Sheppard et al., 1979), long-acting and effects in the tail suspension test and increases Bdnf mRNA highly potent somatostatin analogues are currently available for expression in the mouse cerebral cortex (Nilsson et al., 2012). the treatment of acromegaly and neuroendocrine tumors, includ- ing octreotide (long-acting; LAR-OCT; Bauer et al., 1982) and EFFECTS OF ANTIDEPRESSANTS ON SOMATOSTATIN IN THE CNS Lanreotide (slow release or autogel; Bevan, 2005; Molitch, 2008). Significant efforts have been directed toward the characterization Compared to somatostatin, pharmacological tools of the five of the downstream targets of antidepressant treatment, with a somatostatin receptor subtypes have lagged behind, partly due focus on somatostatin. A recent study demonstrates that chronic to the lack of high-affinity antagonists. imipramine treatment increases somatostatin expression in mouse In addition, several novel somatostatin therapy models are hypothalamus (Nilsson et al., 2012). However, there is incon- available: (1) Universal somatostatin (Schmid and Schoeffter, sistency regarding the effect of chronic citalopram treatment 2004): a somatostatin molecular analog with high binding affin- on somatostatin levels in rats (Kakigi et al., 1992; Prosperini ity to all or most human somatostatin receptors. An exam- et al., 1997; Pallis et al., 2006, 2009). Repeated administration of ple is SOM230, which interacts with Sst1,2,3,5 and particularly imipramine, maprotiline, mianserin, carbamazepine or zotepine potent at Sst5 compared with LAR-OCT; (2) Chimeric somato- has no effect on somatostatin levels in various brain regions of rats statin/dopamine molecule (Saveanu et al., 2002; Pivonello et al., (Weiss et al., 1987; Kakigi et al., 1992). While some somatostatin 2005): a somatostatin and dopamine hybrid agonist, based on receptors seem to exert anxiolytic or antidepressant-like effects, reports that dopamine and somatostatin receptors can hetero- there is no direct evidence supporting somatostatin receptors as oligomerize to enhance functional responses (Rocheville et al., downstream targets of current antidepressants. Together, these 2000). An example is BIM-23A760, which accelerates the suppres- findings suggest that somatostatin levels are mostly unchanged sion of growth hormone and adrenocorticotropic hormone by by antidepressants. It is unclear whether somatostatin, GABA, or the interaction with Sst2 and Drd2 simultaneously; (3) Chimeric- GABA functioning in somatostatin-expressing interneurons may somatostatin vaccinations (Haffer,2012): a fusion protein express- be the real mediators or antidepressant targets. Future studies are ing chloramphenicol acetyl transferase protein and somatostatin. needed to determine the involvement of somatostatin receptors Two somatostatin vaccinations, JH17 and JH18, can effectively and associated intracellular signaling pathways in the therapeu- reduce weight gain and reduce final body weight percentage of tic effects of antidepressants, or whether somatostatin effects are normal, non-obese mice and mice with diet-induced obesity via independent of current antidepressant modalities. the intra-peritoneal route; (4) Non-peptide antagonists, such as SRA880 (Sst1 selective), ACQ090 (Sst3 selective) and Sst4 selective β peptide agonists (Rivier et al., 2003; Hoyer et al., 2004). Despite POTENTIAL MECHANISMS OF SELECTIVE VULNERABILITY this extensive list, the practical use of somatostatin in the brain is OF SOMATOSTATIN-EXPRESSING INTERNEURONS hampered by the multiple effects of the peptide, by the need for It is possible that low somatostatin in diseases acts as a biomarker small molecules targeting specific, high affinity receptors on the for deregulated function of somatostatin-expressing neurons. As target cells in specific brain regions, and by the need for feasible such, it is essential to identify upstream factors responsible for routes of administration that lead to fast delivery into the brain. the dysfunction of somatostatin-expressing interneurons in neu- The potential for using somatostatin analogues as treatment rological disorders. We speculate that intrinsic cellular properties in the CNS is emerging for treatment of epilepsy (Vezzani and in somatostatin-expressing neurons may determine their selec- Hoyer, 1999; Tallent and Qiu, 2008), pain (Mollenholt et al., 1994; tive vulnerability to various insults. Pathways underlying this Taura et al., 1994) and headaches (Sicuteri et al., 1984; Kapicioglu high vulnerability may include high intrinsic oxidative stress et al., 1997); potential use for treatment of mood disorders is sug- related to mitochondria, high sensitivity to inflammation, high gested by reversal of emotion-like behaviors in rodent models. dependence on neurotrophic environment, and cellular devel- Several pharmacological studies support a role of somatostatin in opmental and aging processes. These canonical pathways might affect regulation. Intra-ventricular administration of somatostatin provide novel cell-based perspectives in the treatment of affected in rats produces anxiolytic- and antidepressant-like behaviors somatostatin-expressing cells across neurological disorders. in the elevated plus-maze and forced swim tests, and a neu- rophysiological signature of anxiolytic drugs (e.g., reduction of OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTIONS theta frequency and theta frequency curve slope; Engin et al., Oxidative stress produced by mitochondria during respiration is 2008). Mice with intra-amygdalar and intra-septal microinfusions a common pathogenic mechanism implicated in neurological dis- of somatostatin-14 and somatostatin-28 display reduced anxiety- orders (Sorce and Krause, 2009; Stefanescu and Ciobica, 2012). like behavior in the elevated plus-maze and shock-probe tests Depressed states in mood disorders are associated with decreased

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brain energy generation (Baxter et al., 1985, 1989). Mitochon- episodes (Celik et al., 2010; Maes et al., 2012), suggesting that drial dysfunction together with the oxidative stress accumulation prior depression may sensitize inflammatory responses. Patients has been proposed to synergistically contribute to the neuro- treated with inflammatory cytokines, such as interferon-α,are endangerment processes underlying depression (Gardner et al., at greater risk of developing depressive episodes (Castera et al., 2003; Burnett et al.,2005) and neurodegenerative diseases (Lin and 2006; Lotrich et al., 2007). Somatostatin released from sensory Beal, 2006; Mancuso et al., 2007; Petrozzi et al., 2007). Similarly, nerves and somatostatin receptors on peripheral blood mononu- high baseline oxidative stress could be an intrinsic characteris- clear cells play a crucial role in anti-inflammation through tic of vulnerable neuronal populations. Notably, neuronal nitric inhibition of pro-inflammatory peptide release (Szolcsanyi et al., oxide synthase (nNOS) and NADPH diaphorase (NADPHd), two 1998; Kurnatowska and Pawlikowski, 2000; Helyes et al., 2004). enzymes that produce reactive oxidative species, are extensively Rats with chronic inflammation induced by lipopolysaccharide and almost exclusively co-localized with somatostatin and neu- show decreased hippocampal somatostatin expression (Gavilan ropeptide Y (Dun et al., 1994; Figueredo-Cardenas et al., 1996; et al., 2007). It is possible that there is crosstalk among periph- Jaglin et al., 2012), hence providing a neurochemical basis for eral inflammation, somatostatin function, and central effects high susceptibility of somatostatin-expressing neurons to generate of somatostatin-expressing neurons. Hence, decreasing somato- oxidative stress in response to pathophysiological insults. statin expression due to cellular impairment in the progress of neurological diseases may further enhance inflammation in HIGH DEPENDENCE ON NEUROTROPHIC ENVIRONMENT a vicious cycle, leading to exacerbated cellular vulnerability of Brain-derived neurotrophic factor (BDNF) and its receptor neu- somatostatin-expressing neurons. rotrophic tyrosine kinase receptor type 2 (TrkB) have been Aging is associated with a considerable increase in implicated in mood disorders (Guilloux et al., 2012; Tripp et al., an activated, pro-inflammatory state (Wei et al., 1992; 2012). BDNF-TrkB signaling is one of the key mediators for Bruunsgaard and Pedersen, 2003), a decline in circulating levels maintaining normal somatostatin gene expression (Glorioso et al., of Bdnf (Erickson et al., 2010), and increased oxidative dam- 2006; Martinowich et al., 2011). Progressively impairing BDNF- age (Sohal and Weindruch, 1996). Somatostatin expression is TrkB signaling in patients with mood disturbances may directly significantly decreased with age in human cortical regions, but impact the biology of somatostatin-expressing neurons, resulting parvalbumin expression is not altered by age (Erraji-Benchekroun in somatostatin deficits. In addition, Bdnf-TrkB signaling itself et al., 2005; Glorioso et al., 2011). Similarly, the number of is vulnerable to increased inflammation (Goshen et al., 2008; Koo hippocampal somatostatin-expressing interneurons decreases in and Duman,2008; Song and Wang,2011) and high glucocorticoids aged rats, but the number of parvalbumin-expressing neurons insults (Hodes et al., 2012). Mild oxidative stress inhibits tyrosine remains the same (Vela et al., 2003). Somatostatin and IL-1β phosphatases activity (Barrett et al., 2005), potentially leading to mRNA expression are negatively correlated in aged hippocampus impaired TrkB downstream signaling. Cortistatin and neuropep- of rats (Gavilan et al., 2007). Comparing the effects of aging on tide Y expression partly overlaps with the somatostatin neuron somatostatin expression in the sgACC, an accelerated reduction is population in rodents (Figueredo-Cardenas et al., 1996; de Lecea found in patients with MDD compared to normal aging subjects et al., 1997; Xu et al., 2010). Comparing the profile of gene changes (Tripp et al., 2012), suggesting a pattern resulting in an early aging between subjects with MDD and mice with genetically-altered phenomenon which we have speculated may be synergistically Bdnf signaling suggest that the reduced somatostatin, neuropep- induced by normal age-related changes and depression-related tide Y and cortistatin are partly downstream from a combination pathological change (Douillard-Guilloux et al., 2013). of reduced constitutive and activity-dependent Bdnf signaling (Guilloux et al., 2012). In contrast, markers for other GABA neu- CONCLUSION ron subtypes targeting the perisomatic area region cell body and Here we have focused on somatostatin, a GABA marker, axon initial segment of pyramidal neurons (i.e., cholecystokinin down-regulated in MDD, schizophrenia, bipolar disorder, and and calretinin), appear to be independent of BDNF signaling and neurodegenerative diseases. Exploring cross-disease molecular unaffected in MDD patients (Guilloux et al., 2012; Tripp et al., (somatostatin) and cellular (somatostatin-expressing interneu- 2012). Hence, it is possible that the somatostatin-specific cellu- rons) pathological findings suggests a dimensional pathological lar function and vulnerability are partly mediated by BDNF-TrkB phenotype that is specific to the somatostatin gene/cell biolog- signaling during both physiological and pathological processes of ical entity rather than to categorical brain disorders. Based on affect regulation. these results we speculate that common risk factors affecting somatostatin and somatostatin-expressing neurons may impact INFLAMMATION AND CELLULAR AGING information processing in the cortical local circuits (Figure 1). Inflammation has been implicated as a contributing factor in Clarifying the role of somatostatin and its regulation of GABA the onset and progression of many neurological disorders (Di inhibition in affect regulation could provide new strategies for Filippo et al.,2008). Mood disturbances are associated with an acti- predicting, delaying, and treating neurological diseases with vated inflammatory response system (Padmos et al., 2008; Miller mood disturbances. A number of questions remain. For exam- et al., 2009), including increased levels of peripheral interleukins ple, are the prevalent somatostatin deficits seen in multiple and tumor necrosis factor-alpha in MDD patients (Kaestner diseases reflected in a common symptom dimension, such as et al., 2005; Howren et al., 2009; Dowlati et al., 2010; Maes, low mood, across neurological diseases? What are the critical 2011). Inflammatory illnesses are associated with more depressive events that determine the vulnerability of somatostatin-expressing

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neurons? And what are the pathogenic mechanisms that mediate for several neuropsychiatric disorders and neurodegenerative the observed disease-related molecular and cellular phenotypes? diseases. One possibility is that inflammation, oxidative stress, aging, and reduced neurotrophic support may all converge to affect ACKNOWLEDGMENTS somatostatin-expressing neurons. Targeting these pathways may This work was supported by National Institute of Mental Health exert neuro-protective effects on somatostatin-expressing neu- (NIMH-MH093723, MH084060 and MH077159). We thank rons, as a potential therapeutic approach with implications Beverly French for careful review of the manuscript.

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