GABAergic interneuron origin of schizophrenia pathophysiology.
GABAergic interneuron origin of schizophrenia pathophysiology.
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DOI：
10.1016/j.neuropharm.2011.01.022
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发表时间：
2012-03
影响因子：
4.7
通讯作者：
Belforte, Juan E.
中科院分区：
文献类型：
--
作者：
Nakazawa, Kazu;Zsiros, Veronika;Jiang, Zhihong;Nakao, Kazuhito;Kolata, Stefan;Zhang, Shuqin;Belforte, Juan E.
关键词：
众所周知，全身应用N-甲基-D-天冬氨酸型谷氨酸受体(NMDAR)拮抗剂引起的NMDAR功能低下会导致其他健康受试者出现精神分裂症样症状。然而，导致NMDAR功能低下后出现这些症状的脑区或细胞类型在很大程度上仍不清楚。一种可能性，即所谓的“GABA能起源假说”是，GABA能中间神经元的NMDAR功能低下，特别是足以产生精神分裂症样的效应。在解决这个问题的一种尝试中，产生了转基因小鼠，其中NMDAR从皮质和海马GABA能中间神经元中选择性地删除，其中大多数是小白蛋白(PV)阳性的。这种操作引发了一系列表型--从分子、生理到行为--类似于人类精神分裂症的特征。基于这些结果，结合以前的文献，我们认为在发育过程中，NMDAR在皮质、PV阳性、快速放电的中间神经元功能低下，产生精神分裂症样效应。本文综述了有关精神分裂症患者GABA能(尤其是PV阳性)中间神经元被破坏的资料。PV阳性中间神经元，其中许多呈现快速放电模式，不仅对皮层抑制的严格时间控制至关重要，而且对同步膜电位伽马带振荡的产生也是至关重要的。因此，我们认为在精神分裂症中，控制和同步不同皮质回路的快速放电中间神经元的特定能力被破坏，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侮辱--包括兴奋毒性和氧化应激--的高度脆弱性可能有助于解释它们对精神分裂症发展的重大贡献。
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.
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产后NMDA拮抗剂治疗后，成人前额叶皮层神经元的缺陷和行为。
影响因子：
3.6
作者：
Coleman, Leon G., Jr.;Jarskog, L. Fredrik;Moy, Sheryl S.;Crews, Fulton T.
通讯作者：
Crews, Fulton T.
DOI：
10.1002/cne.22006
发表时间：
2009-06-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Cruz DA;Lovallo EM;Stockton S;Rasband M;Lewis DA
通讯作者：
Lewis DA
影响因子：
64.8
作者：
COBB, SR;BUHL, EH;SOMOGYI, P
通讯作者：
SOMOGYI, P
影响因子：
16.2
作者：
Blatow, M;Rozov, A;Monyer, H
通讯作者：
Monyer, H
DOI：
10.1177/070674378503000407
发表时间：
1985-01-01
影响因子：
4
作者：
BIRD, JM
通讯作者：
BIRD, JM