Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Neuropharmacology. 2012 Mar;62(3):1574-83. doi: 10.1016/j.neuropharm.2011.01.022. Epub 2011 Jan 26.
Hypofunction of N-methyl-d-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell-types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes--from molecular and physiological to behavioral--resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults--including excitotoxicity and oxidative stress--might help to explain their significant contribution to the development of schizophrenia.
众所周知，全身给予 NMDA 型谷氨酸受体（NMDAR）拮抗剂会导致 NMDA 受体功能低下，从而在健康受试者中引起类似精神分裂症的症状。然而，导致这些症状出现的大脑区域或细胞类型在很大程度上仍然未知。一种可能性是所谓的“GABA 能起源假说”，即 GABA 能中间神经元的 NMDAR 功能低下足以产生类似精神分裂症的效应。为了解决这个问题，研究人员生成了转基因小鼠，其中 NMDAR 选择性地从皮质和海马 GABA 能中间神经元中缺失，这些中间神经元大多数为 PV 阳性。这种操作触发了一系列表型——从分子和生理到行为——类似于人类精神分裂症的特征。基于这些结果，并结合以前的文献，我们认为在发育过程中，皮质、PV 阳性、快速放电中间神经元的 NMDAR 功能低下会产生类似精神分裂症的效应。本综述总结了表明在精神分裂症中 GABA 能（特别是 PV 阳性）中间神经元被破坏的证据。PV 阳性中间神经元，其中许多具有快速放电的放电模式，不仅对于皮质抑制的紧密时间控制至关重要，而且对于同步膜电位 γ 波段振荡的产生也至关重要。因此，我们认为在精神分裂症中，快速放电中间神经元控制和同步不同皮质回路的特定能力被破坏，这种破坏可能是许多精神分裂症症状的基础。我们进一步认为，皮质边缘快速放电中间神经元对遗传易感性和早期环境损伤（包括兴奋性毒性和氧化应激）的高度易感性可能有助于解释它们对精神分裂症发展的重要贡献。
