Leonard S, Adams C, Breese C R, Adler L E, Bickford P, Byerley W, Coon H, Griffith J M, Miller C, Myles-Worsley M, Nagamoto H T, Rollins Y, Stevens K E, Waldo M, Freedman R
Dept. of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Schizophr Bull. 1996;22(3):431-45. doi: 10.1093/schbul/22.3.431.
Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.
精神分裂症的部分特征可能是感觉加工缺陷。对一种这样的内表型，即P50听觉诱发电位门控缺陷进行的生化、分子和遗传学研究表明，神经元烟碱样受体之一，α7烟碱样受体，可能在参与该表型的抑制性神经通路中发挥作用。在非门控受试者中，尼古丁可使P50缺陷恢复正常。尽管大多数精神分裂症患者是重度吸烟者，但尼古丁的作用可能是短暂的，因为已知α7受体可迅速脱敏。在P50门控缺陷的动物模型中，α7烟碱样受体拮抗剂可阻断配对听觉刺激中第二个刺激的正常门控。受体表达的区域定位包括已知在感觉过滤中起作用的区域。海马中的一种抑制机制可能涉及烟碱对γ-氨基丁酸（GABA）能中间神经元的刺激，从而导致对重复刺激的反应降低。在精神分裂症患者死后解剖的海马脑组织中，α7受体的表达降低。P50缺陷在精神分裂症家系中具有遗传性，但它不足以导致疾病发生，因此代表一种易患因素。对多重精神分裂症家系中的P50缺陷与全基因组的脱氧核糖核酸（DNA）标记进行连锁分析，得到了与位于15号染色体上包含α7烟碱样受体基因区域的DNA标记的正对数优势分数。阐明P50与其他已知在疾病病因学中很重要的因素之间可能的相互作用，对于确定精神分裂症的整体病理生物学很重要。
