抑郁症(major depressive disorder)是一种常见的精神疾病,但其病理机制尚不清楚。近年来,研究发现神经网络的兴奋与抑制平衡失调可能是导致抑郁症的重要因素之一,该平衡主要由兴奋性谷氨酸能锥体神经元(pyramidal neuron)和抑制性γ-氨基丁酸(GABA)神经元协调完成。SST中间神经元是主要的抑制神经元,调节锥体神经元活动,参与应激反应,对应激有较高的易感性,在抑郁症患者背腹侧前额叶(dlPFC)、扣带回(ACC)、海马等脑区皆发现了SST mRNA或蛋白水平降低。本文将综述SST中间神经元功能及其功能降低对抑郁症影响的研究结果,包括在不同脑区(如前额叶、海马等)的表现、起因、相关的抑郁症药物研发。
Major depressive disorder is a common mental illness, but its pathological mechanism is still unclear. In recent years, studies have found that imbalance of neural network excitability and inhibition may be one of the important factors leading to depression, which is mainly caused by the incoordination between excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acid neurons. Somatostatin-expressing interneurons, the main inhibitory neurons, regulate pyramidal neuronal activity, participate in stress response, and have a high susceptibility to stress. In the dorsal ventral frontal lobes (dlPFC), cingulate gyrus (ACC), hippocampus and other brain regions in patients with depression, researchers have found a decrease in SST mRNA and protein levels. This article will review the function of somatostatin-expressing interneuron and how its functional reduction impacts depression, including causes and performance.
抑郁症,GABA能中间神经元,SST中间神经元,前额叶,药物研发, Major Depressive Disorder Gabaergic Interneurons Somatostatin Interneurons Prefrontal Cortex Drug DevelopmentSST中间神经元功能降低对抑郁症的影响
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1. 引言
全球人口中约有5%患有抑郁症(Faron-Gorecka et al., 2016),约有20.6%的人口有患抑郁症的风险(Hasin et al., 2018)。抑郁症是自杀率升高的原因之一(Ebmeier, Donaghey, & Steele, 2006),抑郁症已然成为威胁人类身心健康的重大疾病,因此对其病理生理机制和潜在药物靶点的研究至关重要。
抑郁症的病理机制主要有单胺能假说(Hirschfeld, 2000)、谷氨酸假说(Wang, Jing, Toledo-Salas, & Xu, 2015)、下丘脑–垂体–肾上腺(HPA)轴调节应激反应功能受损假说(Keller et al., 2017; Pariante & Lightman, 2008)。其中,单胺能假说认为抑郁症产生的原因是大脑内单胺类神经递质缺乏,如去甲肾上腺素、5-HT等,基于这一假说研发了SSRI、三环类抗抑郁药物,通过增加大脑单胺水平治疗抑郁症状,其缺点主要是治疗效率低和复发率高(Marathe, D’Almeida P, Virmani, Bathini, & Alberi, 2018)。谷氨酸假说起源于快速抗抑郁药物ketamine (NMDAR受体拮抗剂)的发现,人类研究发现ketamine在2小时内具有快速抗抑郁功效(Zarate et al., 2012),表明抑郁症可能与谷氨酸突触传递及可塑性的缺陷相关(Wang et al., 2015)。在80%抑郁症患者中发现HPA轴活动过度,糖皮质激素调节的HPA轴负反馈缺陷(Vincent et al., 2013),而动物研究发现糖皮质激素受体拮抗剂RU 43044在调节HPA轴活动时能够减少抑郁行为(Ago et al., 2008)。
近年来,对抑郁症患者和动物实验的研究发现兴奋性锥体神经元和抑制性中间神经元之间功能的失衡可能是导致抑郁症的重要病理机制(Thompson et al., 2015)。神经元网络兴奋与抑制失衡可能对神经网络功能、信息处理与传输产生影响。长期的神经网络兴奋与抑制平衡异常可能引发诸多精神疾病临床症状,例如重度抑郁症(MDD)、双相情感障碍(BPD)、焦虑症以及精神分裂症(SCZ)。
在抑郁症患者大脑中发现GABA浓度降低(Gabbay et al., 2012),GABAA型受体(GABAARs)减少(Klumpers et al., 2010),谷氨酸脱羧酶(GAD)表达减少(Banasr et al., 2017)。患者在接受抗抑郁药物治疗(Shen et al., 2010)、电休克治疗(Sanacora et al., 2003)、经颅磁刺激治疗(TMS) (Dubin et al., 2016)或认知行为疗法(Sanacora et al., 2006)后大脑内GABA含量升高,且抑郁症状减轻,说明GABA还参与到抗抑郁作用中。
除了抑郁症,在其他精神障碍中也发现GABA中间神经元抑制功能降低,包括双相情感障碍(Atagun et al., 2017)、精神分裂症(Lewis & Sweet, 2009)等。
作为中间神经元,SST神经元的主要功能在于调节神经网络的兴奋与抑制平衡。SST中间神经元有不同的类型,皮层中主要为Martinotti细胞,分布于皮层第2到第6层(Weckbecker et al., 2003)。在新皮层L1中,SST中间神经元特异性靶向锥体神经元的远端树突(Gentet et al., 2012; Ma, Hu, Berrebi, Mathers, & Agmon, 2006),对传入锥体神经元的兴奋性信号进行局部调节,在控制锥体神经元信息输入中发挥重要作用(Fino et al., 2013; Viollet et al., 2008)。对GIN小鼠和X98小鼠的研究部分阐明了SST中间神经元在大脑皮层中的作用,GIN小鼠的SST中间神经元主要为Martinotti细胞,在皮层第2/3和5层表达绿色荧光蛋白,并投射到第1层,光遗传激活第2、3、5层的SST中间神经元能够抑制锥体神经元放电活动(Xu, Jeong, Tremblay, & Rudy, 2013)。X94小鼠中的GFP表达SST中间神经元细胞主要位于皮层的第4层,为非Martinotti细胞,目标靶向第4层的PV中间神经元,通过抑制PV中间神经元活动激活锥体神经元,同时接受丘脑传入神经信息,光激活第4层的SST中间神经元使得锥体细胞产生去抑制作用(Xu et al., 2013)。
从大量的对抑郁症患各大脑区SST mRNA和含量降低的研究中可以推测抑郁患者SST中间神经元功能缺陷(Douillard-Guilloux, Lewis, Seney, & Sibille, 2017; Guilloux et al., 2012; Sibille et al., 2011; Tripp et al., 2011; Tripp et al., 2012),在啮齿类动物研究中也有同样发现(Lin & Sibille, 2015)。
Fuchs等人的研究对揭示SST中间神经元调节的神经网络兴奋与抑制平衡对抑郁症的影响发挥了重要作用。通过Cre-loxp技术条件性敲除小鼠前脑SST中间神经元中GABAA受体的γ2亚基基因,增加SST中间神经元的抑制性突触输入减少兴奋性突触输入增加,海马CA1区锥体神经元和扣带回第2、3层的抑制性突触输入增强,进而抑制锥体神经元的放电活动,在行为上表现为抑郁样行为减少,表明在不改变大脑SST含量的情况下,通过增加从SST中间神经元到锥体神经元的抑制性突触输入能够产生抗抑郁作用(Fuchs et al., 2017)。
在人类抑郁症患者中发现生长抑素水平降低首先出现在对患者脑脊液(CSF)的研究中(Molchan et al., 1991),该症状随着对抑郁症的治疗而改善(Post, Rubinow, Kling, Berrettini, & Gold, 1988)。此外,在抑郁症患者皮质边缘区中发现与生长抑素共标的两种神经肽(神经肽Y和皮质抑素)的表达均显著下降(Tripp et al., 2011; Tripp et al., 2012)。人类研究在抑郁症患者的多个脑区发现了SST含量、SST蛋白水平和SST mRNA表达降低,如背外侧前额叶皮层(dlPFC)、前扣带皮层(sgACC)和杏仁核中(Guilloux et al., 2012; Sibille et al., 2011; Tripp et al., 2011)。
在动物研究中发现生长抑素受体敲除(SSTKO)小鼠表现出焦虑行为增加、皮质酮水平的升高,皮质抑素(Cortistatin)和Gad67的基因表达降低。对缺乏单个SST1-5受体的小鼠的研究有很多,其中对SST2KO的小鼠研究发现其在高架十字迷宫和旷场中焦虑行为增加,在强迫游泳试验中木僵率增加,垂体促肾上腺皮质激素释放增加而SST含量则相对减少(Viollet et al., 2000),同样是SST2 KO小鼠,在慢性不可测应激模型中发现,相较于青年SST2 KO小鼠,老年SST2 KO小鼠表现出更高水平的空间学习能力和记忆力损伤以及焦虑行为,皮质酮水平也更高(Prevot et al., 2018),这说明SST2受体基因的缺失不仅会加剧小鼠对应激源的敏感性,还会对正常的大脑老化过程产生负面影响。SST2受体亚型的激活在大鼠和小鼠中具有强烈的抗焦虑作用(Engin & Treit, 2009; Prevot et al., 2017)。有研究认为,接受慢性应激后,大鼠纹状体和伏隔核(NAcc)中SST2受体结合位点的增加可能是受到了多巴胺D2受体的调节,说明这两种受体共同参与到了慢性应激引起的应激反应中(Faron-Gorecka et al., 2018),另有研究发现在接受抗抑郁药地昔帕明(Desipramine) 21天后,多巴胺D2受体和SST5受体异二聚体的形成增加,说明多巴胺D2受体和SST5受体异二聚体可能是抗抑郁作用的潜在介质(Szafran-Pilch et al., 2017)。
研究发现SSTR4KO小鼠在高架十字迷宫中焦虑行为增加,在强迫游泳实验中木僵水平上升,而在腹腔注射SST4受体激动剂J-2156后发现小鼠焦虑水平降低,悬尾测试中的抑郁行为减少,同时增加杏仁核、背侧中缝核、导水管周围灰质等脑区Fos免疫反应(Scheich et al., 2016)。近期动物研究发现SST4基因缺失的小鼠对慢性应激诱发的行为和神经内分泌改变具有较高的易感性(Scheich et al., 2017)。
在前额叶皮层(PFC)中,对抑郁症患者大脑组织研究发现,PFC中GABA合成酶GAD67mRNA和蛋白水平减少(Karolewicz et al., 2010),在抑郁症患者的dlPFC中发现SST mRNA表达显著降低(Sibille et al., 2011),使用化学遗传技术急性抑制额叶SST中间神经元活动使得小鼠行为情绪异常增加,而慢性抑制额叶SST中间神经元活动却能够有效地抑制行为情绪异常,这表明SST中间神经元有调节情绪的作用,并且行为情绪调节可能涉及到复杂的神经网络功能(Soumier & Sibille, 2014)。
杏仁核是情绪调节的皮质边缘环路的关键组成部分,在抑郁症患者杏仁核中发现GABA合成酶GAD67mRNA表达和蛋白水平的减少,在杏仁核外侧和基底内侧发现SST mRNA表达下降(Guilloux et al., 2012)和SST中间神经元数量的减少(Douillard-Guilloux et al., 2017),以及几种GABA转录物的减少,包括GABA合成酶、谷氨酸脱羧酶1(GAD1)和GABA受体亚基GABARA1 (Guilloux et al., 2012),但只在女性患者杏仁核中发现了SST基因表达和蛋白水平降低(Guilloux et al., 2012; Sibille et al., 2009),男性MDD受试者杏仁核中SSTRNA表达无显著变化,这表明女性与男性在抑郁症中的差异。
持续给药丙咪嗪(imipramine) (一种三环类抗抑郁药物)发现在产生抗抑郁作用的同时,SST-14和SST-18(1-11)表达增加,SST1受体拮抗剂SRA880能与丙咪嗪协同作用,可增加大脑皮质中的BDNF mRNA表达,在悬尾试验中引起抗抑郁作用,这可能是由于SST增加血清素释放导致的(Nilsson et al., 2012)。另一项研究发现地昔帕明(desipramine) (一种抗抑郁药物和丙咪嗪的活性代谢物)治疗后,大鼠海马CA1区SST1受体表达增加(Pallis et al., 2009)。
持续给药西酞普兰(citalopram) (一种选择性5-羟色胺再摄取抑制剂抗抑郁药物)发现在尾状核壳、海马、伏隔核和前额叶皮质中SST水平增加,海马CA1区SST1、4受体表达显著增加,而额叶皮质表层和深层的SST2受体密度显着下降,表明西酞普兰在产生抗抑郁效果的同时,还影响生长激素抑制素系统对情绪、动机和认知的功能(Pallis et al., 2009)。
快速抗抑郁药物的研究为抑郁症治疗提供了新的途径,氯胺酮(ketamine)和东莨菪碱(scopolamine)通过快速增加体内谷氨酸水平、BDNF通路激活和突触生成产生快速的抗抑郁作用。研究发现氯胺酮增强内侧前额叶皮质(mPFC)中抑制性突触的作用,进而逆转GABAARγ2+/−小鼠的抑郁行为(Ren et al., 2016),但是氯胺酮会产生游离和拟态副作用,在较高剂量下易上瘾(Machado-Vieira, Salvadore, DiazGranados, & Zarate, 2009),其药用价值还有待研究。一项小鼠实验中发现,东莨菪碱通过拮抗mPFC SST中间神经元中代谢型乙酰胆碱受体(mAChR)起到抗抑郁作用(Wohleb et al., 2016),这似乎与抑郁症相关SST降低的研究证据不一致,其速效抗抑郁药疗效还需进一步证实。此外,最近的一项研究表明,内侧前额叶皮质的生长抑素中间神经元对于氯胺酮的快速作用抗抑郁机制是必需的(Wohleb等,2016)。
郭 沉. SST中间神经元功能降低对抑郁症的影响Effect of Somatostatin-Expressing Interneuron Deficits in Depression[J]. 心理学进展, 2019, 09(10): 1767-1777. https://doi.org/10.12677/AP.2019.910214
参考文献ReferencesAgo, Y., Arikawa, S., Yata, M., Yano, K., Abe, M., Takuma, K., & Matsuda, T. (2008). Antidepressant-Like Effects of the Glucocorticoid Receptor Antagonist RU-43044 Are Associated with Changes in Prefrontal Dopamine in Mouse Models of Depression. Neuropharmacology, 55, 1355-1363. https://doi.org/10.1016/j.neuropharm.2008.08.026Atagun, M. I., Sikoglu, E. M., Soykan, C., Serdar Suleyman, C., Ulusoy-Kaymak, S., Caykoylu, A., Moore, C. M. et al. (2017). Perisylvian GABA Levels in Schizophrenia and Bipolar Disorder. Neuroscience Letters, 637, 70-74. https://doi.org/10.1016/j.neulet.2016.11.051Banasr, M., Lepack, A., Fee, C., Duric, V., Maldonado-Aviles, J., DiLeone, R., Sanacora, G. et al. (2017). Characterization of GABAergic Marker Expression in the Chronic Unpredictable Stress Model of Depression. Chronic Stress (Thousand Oaks), 1. https://doi.org/10.1177/2470547017720459Barja, G. (2002). Endogenous Oxidative Stress: Relationship to Aging, Longevity and Caloric Restriction. Ageing Research Reviews, 1, 397-411. https://doi.org/10.1016/S1568-1637(02)00008-9Bowley, M. P., Drevets, W. C., Ongur, D., & Price, J. L. (2002). Low Glial Numbers in the Amygdala in Major Depressive Disorder. Biological Psychiatry, 52, 404-412. https://doi.org/10.1016/S0006-3223(02)01404-XBrown, M. R., Rivier, C., & Vale, W. (1984). Central Nervous System Regulation of Adrenocorticotropin Secretion: Role of Somatostatins. Endocrinology, 114, 1546-1549. https://doi.org/10.1210/endo-114-5-1546Bruunsgaard, H., & Pedersen, B. K. (2003). Age-Related Inflammatory Cytokines and Disease. Immunology and Allergy Clinics of North America, 23, 15-39. https://doi.org/10.1016/S0889-8561(02)00056-5Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G. M. (2004). Lower Hippocampal Volume in Patients Suffering from Depression: A Meta-Analysis. American Journal of Psychiatry, 161, 598-607. https://doi.org/10.1176/appi.ajp.161.4.598Czeh, B., Varga, Z. K., Henningsen, K., Kovacs, G. L., Miseta, A., & Wiborg, O. (2015). Chronic Stress Reduces the Number of GABAergic Interneurons in the Adult Rat Hippocampus, Dorsal-Ventral and Region-Specific Differences. Hippocampus, 25, 393-405. https://doi.org/10.1002/hipo.22382Douillard-Guilloux, G., Guilloux, J. P., Lewis, D. A., & Sibille, E. (2013). Anticipated Brain Molecular Aging in Major Depression. The American Journal of Geriatric Psychiatry, 21, 450-460. https://doi.org/10.1016/j.jagp.2013.01.040Douillard-Guilloux, G., Lewis, D., Seney, M. L., & Sibille, E. (2017). Decrease in Somatostatin-Positive Cell Density in the Amygdala of Females with Major Depression. Depress Anxiety, 34, 68-78. https://doi.org/10.1002/da.22549Du, X., Serena, K., Hwang, W., Grech, A. M., Wu, Y. W. C., Schroeder, A., & Hill, R. A. (2018). Prefrontal Cortical Parvalbumin and Somatostatin Expression and Cell Density Increase during Adolescence and Are Modified by BDNF and Sex. Molecular and Cellular Neuroscience, 88, 177-188. https://doi.org/10.1016/j.mcn.2018.02.001Dubin, M. J., Mao, X., Banerjee, S., Goodman, Z., Lapidus, K. A., Kang, G., Shungu, D. C. et al. (2016). Elevated Prefrontal Cortex GABA in Patients with Major Depressive Disorder after TMS Treatment Measured with Proton Magnetic Resonance Spectroscopy. Journal of Psychiatry & Neuroscience, 41, E37-E45. https://doi.org/10.1503/jpn.150223Ebmeier, K. P., Donaghey, C., & Steele, J. D. (2006). Recent Developments and Current Controversies in Depression. The Lancet, 367, 153-167. https://doi.org/10.1016/S0140-6736(06)67964-6Engin, E., & Treit, D. (2009). Anxiolytic and Antidepressant Actions of Somatostatin: The Role of sst2 and sst3 Receptors. Psychopharmacology (Berl), 206, 281-289. https://doi.org/10.1007/s00213-009-1605-5Engin, E., Stellbrink, J., Treit, D., & Dickson, C. T. (2008). Anxiolytic and Antidepressant Effects of Intracerebroventricularly Administered Somatostatin: Behavioral and Neurophysiological Evidence. Neuroscience, 157, 666-676. https://doi.org/10.1016/j.neuroscience.2008.09.037Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Heo, S., McLaren, M., Kramer, A. F. et al. (2010). Brain-Derived Neurotrophic Factor Is Associated with Age-Related Decline in Hippocampal Volume. Journal of Neuroscience, 30, 5368-5375. https://doi.org/10.1523/JNEUROSCI.6251-09.2010Erraji-Benchekroun, L., Underwood, M. D., Arango, V., Galfalvy, H., Pavlidis, P., Smyrniotopoulos, P., Sibille, E. et al. (2005). Molecular Aging in Human Prefrontal Cortex Is Selective and Continuous throughout Adult Life. Biological Psychiatry, 57, 549-558. https://doi.org/10.1016/j.biopsych.2004.10.034Faron-Gorecka, A., Kusmider, M., Kolasa, M., Zurawek, D., Szafran-Pilch, K., Gruca, P., Dziedzicka-Wasylewska, M. et al. (2016). Chronic Mild Stress Alters the Somatostatin Receptors in the Rat Brain. Psychopharmacology (Berl), 233, 255-266. https://doi.org/10.1007/s00213-015-4103-yFaron-Gorecka, A., Kusmider, M., Solich, J., Kolasa, M., Pabian, P., Gruca, P., Dziedzicka-Wasylewska, M. et al. (2018). Regulation of Somatostatin Receptor 2 in the Context of Antidepressant Treatment Response in Chronic Mild Stress in Rat. Psychopharmacology (Berl), 235, 2137-2149. https://doi.org/10.1007/s00213-018-4912-xFino, E., Packer, A. M., & Yuste, R. (2013). The Logic of Inhibitory Connectivity in the Neocortex. Neuroscientist, 19, 228-237. https://doi.org/10.1177/1073858412456743Fisher, D. A., & Brown, M. R. (1980). Somatostatin Analog: Plasma Catecholamine Suppression Mediated by the Central Nervous System. Endocrinology, 107, 714-718. https://doi.org/10.1210/endo-107-3-714French, L., Ma, T., Oh, H., Tseng, G. C., & Sibille, E. (2017). Age-Related Gene Expression in the Frontal Cortex Suggests Synaptic Function Changes in Specific Inhibitory Neuron Subtypes. Frontiers in Aging Neuroscience, 9, 162. https://doi.org/10.3389/fnagi.2017.00162Fuchs, T., Jefferson, S. J., Hooper, A., Yee, P. H., Maguire, J., & Luscher, B. (2017). Disinhibition of Somatostatin-Positive GABAergic Interneurons Results in an Anxiolytic and Antidepressant-Like Brain State. Molecular Psychiatry, 22, 920-930. https://doi.org/10.1038/mp.2016.188Gabbay, V., Mao, X., Klein, R. G., Ely, B. A., Babb, J. S., Panzer, A. M., Shungu, D. C. et al. (2012). Anterior Cingulate Cortex Gamma-Aminobutyric Acid in Depressed Adolescents: Relationship to Anhedonia. Archives of General Psychiatry, 69, 139-149. https://doi.org/10.1001/archgenpsychiatry.2011.131Gentet, L. J., Kremer, Y., Taniguchi, H., Huang, Z. J., Staiger, J. F., & Petersen, C. C. (2012). Unique Functional Properties of Somatostatin-Expressing GABAergic Neurons in Mouse Barrel Cortex. Nature Neuroscience, 15, 607-612. https://doi.org/10.1038/nn.3051Glorioso, C., Oh, S., Douillard, G. G., & Sibille, E. (2011). Brain Molecular Aging, Promotion of Neurological Disease and Modulation by Sirtuin 5 Longevity Gene Polymorphism. Neurobiology of Disease, 41, 279-290. https://doi.org/10.1016/j.nbd.2010.09.016Glorioso, C., Sabatini, M., Unger, T., Hashimoto, T., Monteggia, L. M., Lewis, D. A., & Mirnics, K. (2006). Specificity and Timing of Neocortical Transcriptome Changes in Response to BDNF Gene Ablation during Embryogenesis or Adulthood. Molecular Psychiatry, 11, 633-648. https://doi.org/10.1038/sj.mp.4001835Gonchar, Y., & Burkhalter, A. (1997). Three Distinct Families of GABAergic Neurons in Rat Visual Cortex. Cerebral Cortex, 7, 347-358. https://doi.org/10.1093/cercor/7.4.347Goshen, I., Kreisel, T., Ben-Menachem-Zidon, O., Licht, T., Weidenfeld, J., Ben-Hur, T., & Yirmiya, R. (2008). Brain Interleukin-1 Mediates Chronic Stress-Induced Depression in Mice via Adrenocortical Activation and Hippocampal Neurogenesis Suppression. Molecular Psychiatry, 13, 717-728. https://doi.org/10.1038/sj.mp.4002055Guilloux, J. P., Douillard-Guilloux, G., Kota, R., Wang, X., Gardier, A. M., Martinowich, K., Sibille, E. et al. (2012). Molecular Evidence for BDNF- and GABA-Related Dysfunctions in the Amygdala of Female Subjects with Major Depression. Molecular Psychiatry, 17, 1130-1142. https://doi.org/10.1038/mp.2011.113Hasin, D. S., Sarvet, A. L., Meyers, J. L., Saha, T. D., Ruan, W. J., Stohl, M., & Grant, B. F. (2018). Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry, 75, 336-346. https://doi.org/10.1001/jamapsychiatry.2017.4602Herman, J. P., Ostrander, M. M., Mueller, N. K., & Figueiredo, H. (2005). Limbic System Mechanisms of Stress Regulation: Hypothalamo-Pituitary-Adrenocortical Axis. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 29, 1201-1213. https://doi.org/10.1016/j.pnpbp.2005.08.006Hirschfeld, R. M. (2000). History and Evolution of the Monoamine Hypothesis of Depression. The Journal of Clinical Psychiatry, 61, 4-6.Hu, W., Zhang, M., Czeh, B., Flugge, G., & Zhang, W. (2010). Stress Impairs GABAergic Network Function in the Hippocampus by Activating Nongenomic Glucocorticoid Receptors and Affecting the Integrity of the Parvalbumin-Expressing Neuronal Network. Neuropsychopharmacology, 35, 1693-1707. https://doi.org/10.1038/npp.2010.31Jaglin, X. H., Hjerling-Leffler, J., Fishell, G., & Batista-Brito, R. (2012). The Origin of Neocortical Nitric Oxide Synthase-Expressing Inhibitory Neurons. Frontiers in Neural Circuits, 6, 44. https://doi.org/10.3389/fncir.2012.00044Karolewicz, B., Maciag, D., O’Dwyer, G., Stockmeier, C. A., Feyissa, A. M., & Rajkowska, G. (2010). Reduced Level of Glutamic Acid Decarboxylase-67 kDa in the Prefrontal Cortex in Major Depression. International Journal of Neuropsychopharmacology, 13, 411-420. https://doi.org/10.1017/S1461145709990587Keller, J., Gomez, R., Williams, G., Lembke, A., Lazzeroni, L., Murphy, G. M., & Schatzberg, A. F. (2017). HPA Axis in Major Depression: Cortisol, Clinical Symptomatology and Genetic Variation Predict Cognition. Molecular Psychiatry, 22, 527-536. https://doi.org/10.1038/mp.2016.120Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., National Comorbidity Survey, R. et al. (2003). The Epidemiology of Major Depressive Disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA, 289, 3095-3105. https://doi.org/10.1001/jama.289.23.3095Klumpers, U. M., Veltman, D. J., Drent, M. L., Boellaard, R., Comans, E. F., Meynen, G., Hoogendijk, W. J. et al. (2010). Reduced Parahippocampal and Lateral Temporal GABAA-[11C]flumazenil Binding in Major Depression: Preliminary Results. European Journal of Nuclear Medicine and Molecular Imaging, 37, 565-574. https://doi.org/10.1007/s00259-009-1292-9Lewis, D. A., & Sweet, R. A. (2009). Schizophrenia from a Neural Circuitry Perspective: Advancing toward Rational Pharmacological Therapies. The Journal of Clinical Investigation, 119, 706-716. https://doi.org/10.1172/JCI37335Li, W., Papilloud, A., Lozano-Montes, L., Zhao, N., Ye, X., Zhang, X., Rainer, G. et al. (2018). Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex. Proteomics, 18, e1700408. https://doi.org/10.1002/pmic.201700408Lin, L. C., & Sibille, E. (2013). Reduced Brain Somatostatin in Mood Disorders: A Common Pathophysiological Substrate and Drug Target? Frontiers in Pharmacology, 4, 110. https://doi.org/10.3389/fphar.2013.00110Lin, L. C., & Sibille, E. (2015). Somatostatin, Neuronal Vulnerability and Behavioral Emotionality. Molecular Psychiatry, 20, 377-387. https://doi.org/10.1038/mp.2014.184Ma, Y., Hu, H., Berrebi, A. S., Mathers, P. H., & Agmon, A. (2006). Distinct Subtypes of Somatostatin-Containing Neocortical Interneurons Revealed in Transgenic Mice. Journal of Neuroscience, 26, 5069-5082. https://doi.org/10.1523/JNEUROSCI.0661-06.2006Machado-Vieira, R., Salvadore, G., DiazGranados, N., & Zarate, C. A. (2009). Ketamine and the Next Generation of Antidepressants with a Rapid Onset of Action. Pharmacology & Therapeutics, 123, 143-150. https://doi.org/10.1016/j.pharmthera.2009.02.010Marathe, S. V., D’Almeida P, L., Virmani, G., Bathini, P., & Alberi, L. (2018). Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression. Journal of Experimental Neuroscience, 12, 1179069518789149. https://doi.org/10.1177/1179069518789149Martinowich, K., Schloesser, R. J., Jimenez, D. V., Weinberger, D. R., & Lu, B. (2011). Activity-Dependent Brain-Derived Neurotrophic Factor Expression Regulates Cortistatin-Interneurons and Sleep Behavior. Molecular Brain, 4, 11. https://doi.org/10.1186/1756-6606-4-11Mayberg, H. S. (2002). Modulating Limbic-Cortical Circuits in Depression: Targets of Antidepressant Treatments. Seminars in Clinical Neuropsychiatry, 7, 255-268. https://doi.org/10.1053/scnp.2002.35223McEwen, B. S., Nasca, C., & Gray, J. D. (2016). Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex. Neuropsychopharmacology, 41, 3-23. https://doi.org/10.1038/npp.2015.171Millan, M. J. (2006). Multi-Target Strategies for the Improved Treatment of Depressive States: Conceptual Foundations and Neuronal Substrates, Drug Discovery and Therapeutic Application. Pharmacology & Therapeutics, 110, 135-370. https://doi.org/10.1016/j.pharmthera.2005.11.006Molchan, S. E., Lawlor, B. A., Hill, J. L., Martinez, R. A., Davis, C. L., Mellow, A. M., Sunderland, T. et al. (1991). CSF Monoamine Metabolites and Somatostatin in Alzheimer’s Disease and Major Depression. Biological Psychiatry, 29, 1110-1118. https://doi.org/10.1016/0006-3223(91)90253-IMurayama, M., Perez-Garci, E., Nevian, T., Bock, T., Senn, W., & Larkum, M. E. (2009). Dendritic Encoding of Sensory Stimuli Controlled by Deep Cortical Interneurons. Nature, 457, 1137-1141. https://doi.org/10.1038/nature07663Nilsson, A., Stroth, N., Zhang, X., Qi, H., Falth, M., Skold, K., Svenningsson, P. et al. (2012). Neuropeptidomics of Mouse Hypothalamus after Imipramine Treatment Reveal Somatostatin as a Potential Mediator of Antidepressant Effects. Neuropharmacology, 62, 347-357. https://doi.org/10.1016/j.neuropharm.2011.08.004Pallis, E., Vasilaki, A., Fehlmann, D., Kastellakis, A., Hoyer, D., Spyraki, C., & Thermos, K. (2009). Antidepressants Influence Somatostatin Levels and Receptor Pharmacology in Brain. Neuropsychopharmacology, 34, 952-963. https://doi.org/10.1038/npp.2008.133Pariante, C. M., & Lightman, S. L. (2008). The HPA Axis in Major Depression: Classical Theories and New Developments. Trends in Neurosciences, 31, 464-468. https://doi.org/10.1016/j.tins.2008.06.006Ponomarev, I., Rau, V., Eger, E. I., Harris, R. A., & Fanselow, M. S. (2010). Amygdala Transcriptome and Cellular Mechanisms Underlying Stress-Enhanced Fear Learning in a Rat Model of Posttraumatic Stress Disorder. Neuropsychopharmacology, 35, 1402-1411. https://doi.org/10.1038/npp.2010.10Post, R. M., Rubinow, D. R., Kling, M. A., Berrettini, W., & Gold, P. W. (1988). Neuroactive Substances in Cerebrospinal Fluid. Normal and Pathological Regulatory Mechanisms. Annals of the New York Academy of Sciences, 531, 15-28. https://doi.org/10.1111/j.1749-6632.1988.tb31808.xPrevot, T. D., Gastambide, F., Viollet, C., Henkous, N., Martel, G., Epelbaum, J., Guillou, J. L. et al. (2017). Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality. Neuropsychopharmacology, 42, 1647-1656. https://doi.org/10.1038/npp.2016.281Prevot, T. D., Viollet, C., Epelbaum, J., Dominguez, G., Beracochea, D., & Guillou, J. L. (2018). sst2-Receptor Gene Deletion Exacerbates Chronic Stress-Induced Deficits: Consequences for Emotional and Cognitive Ageing. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 86, 390-400. https://doi.org/10.1016/j.pnpbp.2018.01.022Rajkowska, G., Halaris, A., & Selemon, L. D. (2001). Reductions in Neuronal and Glial Density Characterize the Dorsolateral Prefrontal Cortex in Bipolar Disorder. Biological Psychiatry, 49, 741-752. https://doi.org/10.1016/S0006-3223(01)01080-0Ren, Z., Pribiag, H., Jefferson, S. J., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B. (2016). Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment. Biological Psychiatry, 80, 457-468. https://doi.org/10.1016/j.biopsych.2016.02.009Rozycka, A., & Liguz-Lecznar, M. (2017). The Space Where Aging Acts: Focus on the GABAergic Synapse. Aging Cell, 16, 634-643. https://doi.org/10.1111/acel.12605Rudy, B., Fishell, G., Lee, S., & Hjerling-Leffler, J. (2011). Three Groups of Interneurons Account for Nearly 100% of Neocortical GABAergic Neurons. Developmental Neurobiology, 71, 45-61. https://doi.org/10.1002/dneu.20853Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Fava, M. et al. (2006). Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. American Journal of Psychiatry, 163, 1905-1917. https://doi.org/10.1176/ajp.2006.163.11.1905Sanacora, G., Fenton, L. R., Fasula, M. K., Rothman, D. L., Levin, Y., Krystal, J. H., & Mason, G. F. (2006). Cortical Gamma-Aminobutyric Acid Concentrations in Depressed Patients Receiving Cognitive Behavioral Therapy. Biological Psychiatry, 59, 284-286. https://doi.org/10.1016/j.biopsych.2005.07.015Sanacora, G., Mason, G. F., Rothman, D. L., Hyder, F., Ciarcia, J. J., Ostroff, R. B., Krystal, J. H. et al. (2003). Increased Cortical GABA Concentrations in Depressed Patients Receiving ECT. American Journal of Psychiatry, 160, 577-579. https://doi.org/10.1176/appi.ajp.160.3.577Scheich, B., Cseko, K., Borbely, E., Abraham, I., Csernus, V., Gaszner, B., & Helyes, Z. (2017). Higher Susceptibility of Somatostatin 4 Receptor Gene-Deleted Mice to Chronic Stress-Induced Behavioral and Neuroendocrine Alterations. Neuroscience, 346, 320-336. https://doi.org/10.1016/j.neuroscience.2017.01.039Scheich, B., Gaszner, B., Kormos, V., Laszlo, K., Adori, C., Borbely, E., Helyes, Z. et al. (2016). Somatostatin Receptor Subtype 4 Activation Is Involved in Anxiety and Depression-Like Behavior in Mouse Models. Neuropharmacology, 101, 204-215. https://doi.org/10.1016/j.neuropharm.2015.09.021Seney, M. L., Chang, L. C., Oh, H., Wang, X., Tseng, G. C., Lewis, D. A., & Sibille, E. (2013). The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes across Species. Frontiers in Psychiatry, 4, 104. https://doi.org/10.3389/fpsyt.2013.00104Seney, M. L., Tripp, A., McCune, S., Lewis, D. A., & Sibille, E. (2015). Laminar and Cellular Analyses of Reduced Somatostatin Gene Expression in the Subgenual Anterior Cingulate Cortex in Major Depression. Neurobiology of Disease, 73, 213-219. https://doi.org/10.1016/j.nbd.2014.10.005Sheline, Y. I. (1996). Hippocampal Atrophy in Major Depression: A Result of Depression-Induced Neurotoxicity? Molecular Psychiatry, 1, 298-299.Shen, Q., Lal, R., Luellen, B. A., Earnheart, J. C., Andrews, A. M., & Luscher, B. (2010). Gamma-Aminobutyric Acid-Type A Receptor Deficits Cause Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Antidepressant Drug Sensitivity Reminiscent of Melancholic Forms of Depression. Biological Psychiatry, 68, 512-520. https://doi.org/10.1016/j.biopsych.2010.04.024Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002). Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression. Journal of Neuroscience, 22, 3251-3261. https://doi.org/10.1523/JNEUROSCI.22-08-03251.2002Sibille, E., Morris, H. M., Kota, R. S., & Lewis, D. A. (2011). GABA-Related Transcripts in the Dorsolateral Prefrontal Cortex in Mood Disorders. International Journal of Neuropsychopharmacology, 14, 721-734. https://doi.org/10.1017/S1461145710001616Sibille, E., Wang, Y., Joeyen-Waldorf, J., Gaiteri, C., Surget, A., Oh, S., Lewis, D. A. et al. (2009). A Molecular Signature of Depression in the Amygdala. American Journal of Psychiatry, 166, 1011-1024. https://doi.org/10.1176/appi.ajp.2009.08121760Song, C., & Wang, H. (2011). Cytokines Mediated Inflammation and Decreased Neurogenesis in Animal Models of Depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 760-768. https://doi.org/10.1016/j.pnpbp.2010.06.020Soumier, A., & Sibille, E. (2014). Opposing Effects of Acute versus Chronic Blockade of Frontal Cortex Somatostatin-Positive Inhibitory Neurons on Behavioral Emotionality in Mice. Neuropsychopharmacology, 39, 2252-2262. https://doi.org/10.1038/npp.2014.76Szafran-Pilch, K., Faron-Gorecka, A., Kolasa, M., Zurawek, D., Szlachta, M., Solich, J., Dziedzicka-Wasylewska, M. et al. (2017). Antidepressants Promote Formation of Heterocomplexes of Dopamine D2 and Somatostatin Subtype 5 Receptors in the Mouse Striatum. Brain Research Bulletin, 135, 92-97. https://doi.org/10.1016/j.brainresbull.2017.10.003Thompson Ray, M., Weickert, C. S., Wyatt, E., & Webster, M. J. (2011). Decreased BDNF, trkB-TK+ and GAD67 mRNA Expression in the Hippocampus of Individuals with Schizophrenia and Mood Disorders. Journal of Psychiatry & Neuroscience, 36, 195-203. https://doi.org/10.1503/jpn.100048Thompson, S. M., Kallarackal, A. J., Kvarta, M. D., Van Dyke, A. M., LeGates, T. A., & Cai, X. (2015). An Excitatory Synapse Hypothesis of Depression. Trends in Neurosciences, 38, 279-294. https://doi.org/10.1016/j.tins.2015.03.003Tripp, A., Kota, R. S., Lewis, D. A., & Sibille, E. (2011). Reduced Somatostatin in Subgenual Anterior Cingulate Cortex in Major Depression. Neurobiology of Disease, 42, 116-124. https://doi.org/10.1016/j.nbd.2011.01.014Tripp, A., Oh, H., Guilloux, J. P., Martinowich, K., Lewis, D. A., & Sibille, E. (2012). Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder. American Journal of Psychiatry, 169, 1194-1202. https://doi.org/10.1176/appi.ajp.2012.12020248Valentine, G. W., & Sanacora, G. (2009). Targeting Glial Physiology and Glutamate Cycling in the Treatment of Depression. Biochemical Pharmacology, 78, 431-439. https://doi.org/10.1016/j.bcp.2009.04.008Vincent, M. Y., Hussain, R. J., Zampi, M. E., Sheeran, K., Solomon, M. B., Herman, J. P., Jacobson, L. et al. (2013). Sensitivity of Depression-Like Behavior to Glucocorticoids and Antidepressants Is Independent of Forebrain Glucocorticoid Receptors. Brain Research, 1525, 1-15. https://doi.org/10.1016/j.brainres.2013.05.031Viollet, C., Lepousez, G., Loudes, C., Videau, C., Simon, A., & Epelbaum, J. (2008). Somatostatinergic Systems in Brain: Networks and Functions. Molecular and Cellular Endocrinology, 286, 75-87. https://doi.org/10.1016/j.mce.2007.09.007Viollet, C., Vaillend, C., Videau, C., Bluet-Pajot, M. T., Ungerer, A., L’Heritier, A., Epelbaum, J. et al. (2000). Involvement of sst2 Somatostatin Receptor in Locomotor, Exploratory Activity and Emotional Reactivity in Mice. European Journal of Neuroscience, 12, 3761-3770. https://doi.org/10.1046/j.1460-9568.2000.00249.xWang, J., Jing, L., Toledo-Salas, J. C., & Xu, L. (2015). Rapid-Onset Antidepressant Efficacy of Glutamatergic System Modulators: The Neural Plasticity Hypothesis of Depression. Neuroscience Bulletin, 31, 75-86. https://doi.org/10.1007/s12264-014-1484-6Weckbecker, G., Lewis, I., Albert, R., Schmid, H. A., Hoyer, D., & Bruns, C. (2003). Opportunities in Somatostatin Research: Biological, Chemical and Therapeutic Aspects. Nature Reviews Drug Discovery, 2, 999-1017. https://doi.org/10.1038/nrd1255Wohleb, E. S., Wu, M., Gerhard, D. M., Taylor, S. R., Picciotto, M. R., Alreja, M., & Duman, R. S. (2016). GABA Interneurons Mediate the Rapid Antidepressant-Like Effects of Scopolamine. The Journal of Clinical Investigation, 126, 2482-2494. https://doi.org/10.1172/JCI85033Xu, H., Jeong, H. Y., Tremblay, R., & Rudy, B. (2013). Neocortical Somatostatin-Expressing GABAergic Interneurons Disinhibit the Thalamorecipient Layer 4. Neuron, 77, 155-167. https://doi.org/10.1016/j.neuron.2012.11.004Yeung, M., & Treit, D. (2012). The Anxiolytic Effects of Somatostatin Following Intra-Septal and Intra-Amygdalar Microinfusions Are Reversed by the Selective sst2 Antagonist PRL2903. Pharmacology Biochemistry and Behavior, 101, 88-92. https://doi.org/10.1016/j.pbb.2011.12.012Yeung, M., Engin, E., & Treit, D. (2011). Anxiolytic-Like Effects of Somatostatin Isoforms SST 14 and SST 28 in Two Animal Models (Rattus norvegicus) after Intra-Amygdalar and Intra-Septal Microinfusions. Psychopharmacology (Berl), 216, 557-567. https://doi.org/10.1007/s00213-011-2248-xZarate, C. A., Brutsche, N. E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N., Cravchik, A., Luckenbaugh, D. A. et al. (2012). Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological Psychiatry, 71, 939-946. https://doi.org/10.1016/j.biopsych.2011.12.010