The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acidergic (GABAergic) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder, anxiety disorders, and schizophrenia. Specifically, nearly 3 decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that coexpress the neuropeptide somatostatin (SST). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders and specifically in MDD. We then focus on properties of the cortical microcircuit, where SST-positive GABAergic interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions.

中文翻译：

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抑郁症中生长抑素阳性的γ-氨基丁酸中间神经元缺陷：皮质微电路和治疗前景


外部和内部信号的功能整合构成了信息处理的基础，对于高级认知功能至关重要。这种情况发生在精细调节的皮质微电路中，其功能在细胞水平上通过兴奋性谷氨酸能锥体神经元和抑制​​性γ-氨基丁酸能（GABA能）中间神经元实现平衡。从细胞过程到神经网络活动，兴奋和抑制的平衡在多种神经精神疾病中被破坏，包括重度抑郁症（MDD）、双相情感障碍、焦虑症和精神分裂症。具体而言，近 3 年的研究证明了降低抑制性 GABA 水平和功能在多种疾病中的作用。在 MDD 中，人类尸检和动物研究的最新证据表明，共表达神经肽生长抑素 (SST) 的 GABA 能中间神经元存在选择性脆弱性。细胞类型特异性分子遗传学的进展现已帮助阐明 SST 中间神经元在皮质处理（锥体细胞兴奋性输入的调节）和行为控制（情绪和认知）中的几个重要作用。在这里，我们回顾了各种疾病（特别是重度抑郁症）中 GABA 能缺陷引起的抑制功能改变的证据。然后，我们关注皮质微电路的特性，其中 SST 阳性 GABA 能中间神经元缺陷可能会以多种方式扰乱功能。最后，根据最近的研究，我们讨论了 SST 细胞缺陷的假定起源，以及对治疗方法的影响。 我们得出的结论是，SST 中间神经元的缺陷代表了一种细胞病理学，因此是使 MDD 和其他 SST 细胞和 GABA 功能减少的疾病的抑制功能正常化的有希望的目标。