GABAergic interneuron origin of schizophrenia pathophysiology

NEUROPHARMACOLOGY

卷:62

Review

Nakazawa, Kazu¹  Zsiros, Veronika¹  Jiang, Zhihong¹  Nakao, Kazuhito¹  Kolata, Stefan¹  Zhang, Shuqin¹  Belforte, Juan E.² 

[1] NIMH, Unit Genet Cognit & Behav, US Dept HHS, Bethesda, MD 20892 USA

[2] Univ Buenos Aires, Sch Med, Dept Physiol, Syst Neurosci Grp, RA-1053 Buenos Aires, DF, Argentina

关键词: Schizophrenia;    Fast-spiking interneuron;    NMDA receptor hypofunction;    Parvalbumin;    Oxidative stress;    Transgenic mice;   

DOI  :  10.1016/j.neuropharm.2011.01.022

来源: Elsevier

【 摘 要 】

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. This article is part of a Special Issue entitled 'Schizophrenia'. Published by Elsevier Ltd.

【 授权许可】

Free