Goldman-Rakic P S, Selemon L D
Section of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Schizophr Bull. 1997;23(3):437-58. doi: 10.1093/schbul/23.3.437.
Clinical and experimental research have provided anatomical, pharmacological, and behavioral evidence for a prominent prefrontal dysfunction in schizophrenia. Negative symptoms and behavioral disorganization in the disorder can be understood as a failure in the working memory functions of the prefrontal cortex by which information is updated on a moment-to-moment basis or retrieved from long-term stores, held in mind, and used to guide behavior by ideas, concepts, and stored knowledge. This article recounts efforts to dissect the cellular and circuit basis of working memory with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of the clinical disorder; it includes recent neuropathological findings that indicate that neural dystrophy rather than cell loss predominates in schizophrenia. Evidence from a variety of studies is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical neurons upon which the working memory function of the prefrontal cortex depends. Interactions between monoamines and a compromised cortical circuitry may hold the key to the salience of frontal lobe symptoms in schizophrenia, in spite of widespread pathological changes. We outline several direct and indirect intercellular mechanisms for modulating working memory function in the prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of glutamatergic pyramidal cells and on gamma-aminobutyric acid (GABA) ergic interneurons in the prefrontal cortex. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is a necessary step in unraveling the receptor mechanisms, which could lead to an effective pharmacological treatment of negative and cognitive symptoms, as well as improved insight into the pathophysiological basis of the disorder.
临床和实验研究已经提供了解剖学、药理学和行为学证据，证明精神分裂症存在显著的前额叶功能障碍。该疾病中的阴性症状和行为紊乱可被理解为前额叶皮质工作记忆功能的失败，通过这种功能，信息在瞬间被更新，或从长期存储中检索出来，记在心里，并用于通过想法、概念和存储的知识来指导行为。本文叙述了剖析工作记忆的细胞和回路基础的努力，目的是将从动物模型中正常脑组织研究获得的见解扩展到对临床疾病的理解；其中包括最近的神经病理学发现，表明在精神分裂症中神经萎缩而非细胞丢失占主导。来自各种研究的证据不断积累，表明多巴胺在调节前额叶皮质工作记忆功能所依赖的皮质神经元兴奋性方面起主要作用。尽管存在广泛的病理变化，但单胺与受损的皮质回路之间的相互作用可能是精神分裂症额叶症状突出的关键。我们基于多巴胺受体在前额叶皮质谷氨酸能锥体细胞的远端树突和棘以及γ-氨基丁酸（GABA）能中间神经元上的定位，概述了几种调节前额叶皮质工作记忆功能的直接和间接细胞间机制。理解皮质回路的主要细胞成分——锥体细胞和非锥体细胞之间的相互作用，是阐明受体机制的必要步骤，这可能会带来对阴性和认知症状的有效药物治疗，以及对该疾病病理生理基础的更深入了解。
