A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia

Bendikov, Inna; Nadri, Carmit; Amar, Shirly; Panizzutti, Rogério; Miranda, Joari De; Wolosker, Herman; Agam, Galila

doi:10.1016/j.schres.2006.10.010

Cited by 297 publications

(211 citation statements)

References 40 publications

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“…The enzymatic consequences of the DAAO mutation are not known, but a postmortem study revealed elevated levels of DAAO in the hippocampus of patients with schizophrenia that correlated with the duration of illness [138]. This would account for the observed reduction of D-serine levels, a reduction that would produce NMDAR hypofunction [139].…”

Section: Daaomentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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Section: Daaomentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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“…D-serine is enriched in corticolimbic regions of the brain, where its localization closely parallels that of NMDARs (30). Genetic and biochemical findings suggest that serine racemase (SR), the enzyme that converts L-serine to D-serine, and D-serine itself are reduced in schizophrenia (31)(32)(33)(34)(35).…”

mentioning

confidence: 99%

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Balu

Puhl

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

196

201

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Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

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“…Долгое время считалось, что исклю-чительно астроциты экспрессируют фермент серинраце-мазу, осуществляющий превращение L-серина в D-серин [52], хотя появились данные, что фермент присутствует и в нейронах [53]. Снижение уровня D-серина обнаружено в сыворотке крови и ЦСЖ больных шизофренией [54][55][56], хотя некоторым исследователям [57] не удалось под-твердить эти данные. T. Ohnuma и соавт.…”

Section: роль астроцитов в нарушениях обмена эндогенных агонистов и аunclassified

“…[54] обнаружили в гиппокампе снижение концентрации D-серина, а также содержания белка фермента серинрацемазы и повышение -D-аминооксидазы (фермент, расщепляющий D-серин). Однако, по данным A. Steffek и соавт.…”

Section: роль астроцитов в нарушениях обмена эндогенных агонистов и аunclassified

Role of astrocytes in alterations of glutamatergic neurotransmission in schizophrenia

Kolomeets

2015

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Представления о том, что в основе шизофрении ле-жит нарушение синаптических межнейрональных связей в пределах нейрохимических систем мозга, являются наи-более распространенными в том разделе биологической психиатрии, который касается патогенеза этого тяжелого заболевания.Нейромедиаторные гипотезы шизофрении (дофамин-ергическая, глутаматергическая и др.) появились еще в середине прошлого века. И если вторая его половина была посвящена в основном разработке дофаминергической гипотезы, то в настоящее время наиболее активно разра-батываемой стала глутаматергическая гипотеза шизофре-нии. В самом общем виде она может быть сформулирова-на как предположение, что в основе нарушений нейроме-диации при шизофрении лежит гипофункция NMDA(Nmethyl-D-aspartate)-рецепторов глутамата [1]. Первона-чально она основывалась на фармакологических данных о том, что антагонисты NMDA-рецепторов (например, фенциклидин) способны вызывать поведенческие нару-шения у человека, сходные с клиническими проявления-ми шизофрении, и усиливать клинические проявления Глутаматергическая гипотеза патогенеза шизофрении основана на предположении, что в основе заболевания лежит гипофункция NMDA(NmethylDaspartate) -рецепторов глутамата. Она в настоящее время является одной из наиболее активно разрабатываемых, поскольку способна объяснить развитие позитивных, негативных симптомов и когнитивных расстройств. В обзоре представлен нейморфологический аспект гипотезы, связанный с функцией астроцитарной глии. Изложены данные литературы, касающейся способности астроцитов регулировать глутаматергическую нейромедиацию. Дисфункция астроцитов при шизофрении связана с нарушениями обратного захвата синаптического глутамата, его рециклинга, а также метаболизма ряда эндогенных лигандов NMDAрецепторов. В статье анализируются также данные экспериментальных и клинических исследований по использованию эндогенных агонистов NMDAрецепторов, а также веществ, способных воздействовать на их транспортеры и ферменты метаболизма, для лечения шизофрении. Подчеркивается, что возможность использования большинства соответствующих веществ в фармакотерапии шизофрении требует дальнейшего изучения. Ключевые слова: астроциты, глутаматергическая нейромедиация, шизофрения.The glutamatergic hypothesis of schizophrenia based on the hypofunction of the NmethylDaspartatetype glutamate receptors (NMDAR) is one of the most widely implicated hypothesis that explains the origin of positive and negative symptoms of illness as well as cognitive deficits. The author considered a neuromorphological aspect of this hypothesis related to the glial astrocytes function. The literature on the astrocyte ability to regulate glutamate neurotransmission is reviewed. Astrocyte abnormalities in schizophrenia include the disturbances of glutamate reuptake, recycling and turnover of endogenous NMDAR ligands. The results of experimental and clinical studies that target levels of endogenous NMDAR ligands, their enzymes and transporters for treatment of schizophrenia symptoms are discussed. Further studies are needed to devel...

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A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia

Cited by 297 publications

References 40 publications

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Role of astrocytes in alterations of glutamatergic neurotransmission in schizophrenia

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