The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

被引：0
作者：
L Verrall
P W J Burnet
J F Betts
P J Harrison
机构：
[1] University of Oxford,Department of Psychiatry
[2] Warneford Hospital,undefined
来源：
Molecular Psychiatry | 2010年 / 15卷
关键词：
-amino acid; DAO; NMDA receptor; schizophrenia; glutamate; -serine;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?
引用
收藏
页码：122 / 137
页数：15
相关论文
共 980 条
[51]  
Freitas ME(2007)Sensitive determination of D-amino acids in mammals and the effect of D-amino-acid oxidase activity on their amounts Biol Psychiatry 62 1310-1316
[52]  
Vargas-Lopes C(2008)Increased levels of glutamate in brains from patients with mood disorders Neurosci Lett 445 53-57
[53]  
Wolosker H(2009)D-amino acids in rat brain measured by liquid chromatography/tandem mass spectrometry Pharmacol Biochem Behav 91 610-620
[54]  
Panizzutti R(2009)Mutant mice with reduced NMDA-NR1 glycine affinity or lack of D-amino acid oxidase function exhibit altered anxiety-like behaviors J Chromatog B 877 2506-2512
[55]  
Fukui K(1999)Determination of D-serine and D-alanine in the tissues and physiological fluids of mice with various D-amineo-acid oxidase activities using two-dimensional high-performance liquid chromatography with fluorescence detection Proc Natl Acad Sci USA 96 721-725
[56]  
Miyake Y(1999)Purification of serine racemase: biosynthesis of the neuromodulator D-serine Proc Natl Acad Sci USA 96 13409-13414
[57]  
Tada M(2004)Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission Eur J Pharmacol 495 153-158
[58]  
Fukui K(1997)Effect of systemic administration of D-serine on the levels of D- and L-serine in several brain areas and periphery of rat Biochem Biophys Res Commun 235 26-30
[59]  
Momoi K(2006)The origin and turnover of D-serine in brain J Chromatogr A 1106 159-164
[60]  
Miyake Y(2008)Sensitive high-performance liquid chromatographic assay for D-amino-acid oxidase activity in mammalian tissues using a fluorescent non-natural substrate, 5-fluoro-D-tryptophan FEBS J 275 3514-3526
12345678910