NMDA receptors and schizophrenia

Kristiansen, Lars V.; Huerta, Ibone; Beneyto, Manuel Gómez; Meador‐Woodruff, James H.

doi:10.1016/j.coph.2006.08.013

Cited by 211 publications

(163 citation statements)

References 82 publications

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“…Increasing evidence implicates NMDA receptor dysregulation in schizophrenia, initially based on clinical evidence that non-competitive antagonists of N-methyl-D-aspartic acid receptors can be psychomimetic (Allen and Young, 1978; Kristiansen et al, 2007;Lahti et al, 1995aLahti et al, , b, 2001Luby et al, 1959;Meador-Woodruff and Healy, 2000;Svenningsson et al, 2003). Our present data suggest dysregulated localization and function of NMDA receptors.…”

Section: Discussionsupporting

confidence: 55%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

136

102

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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Section: Discussionsupporting

confidence: 55%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

136

102

View full text Add to dashboard Cite

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“…There are several post-mortem studies and neuropathological findings, which support the hypothesis that disruption in the normal functioning of the glutamatergic system, contribute to the "symptomatic manifestations of schizophrenia" (reviewed in Kristiansen et al 2007). …”

Section: Introductionmentioning

confidence: 80%

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Neill

Barnes

Cook

et al. 2010

Pharmacology & Therapeutics

477

322

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Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro-and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive disturbances of relevance to schizophrenia in rodents and their subsequent reversal by first-and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-choice serial reaction time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel therapies for improved therapy of cognitive deficits and negative symptoms in schizophrenia.

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“…Further studies will be necessary to further test this hypothesis. Dysregulations of NMDAR subunits are also associated with different neurological and psychiatric disorders, such as epilepsy (40) and schizophrenia (41), and we hypothesize that this dysregulation might potentially account for some of the malfunctions observed in patients with AF9 mutation.…”

Section: Discussionmentioning

confidence: 99%

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Büttner

Johnsen

Kügler

et al. 2010

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

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Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.A F9/MLLT3 is one of multiple fusion partners of the histone methyltransferase MLL1 in acute leukemia (1, 2). However, mutations of the AF9/MLLT3 gene alone are not associated with leukemia but are implicated in anterior homeotic transformations during mouse development (3), and in neurodevelopmental diseases, such as mental retardation, epilepsy, and ataxia in human patients (4,5). Little is known about AF9 function in the CNS, although its expression pattern implies a role during development of the forebrain and cerebellum (6). In the mouse forebrain, Af9 is transcribed in the subventricular zone (SVZ), a neurogenic compartment that harbors progenitors for upper layer neurons (7,8). Af9 is also expressed in neurons dispersed over all cortical layers and diverges in this respect from other SVZ markers, such as Svet1 and Cux2 (6). On the molecular level, AF9 mediates transcriptional activation and was classified as a proto-oncogene (9). The AF9 protein interacts with many different factors and has been implicated in different cellular processes (9-11). In the extensive network of interacting proteins, AF9 associates with DOT1L (12, 13), the main enzyme responsible for histone H3 methylation at lysine 79 (14-16). Dot1 is implicated in UV damage repair (17), and affects gene expression in yeast, flies, and mammals (18, 19), whereas histone H3 lysine 79 (H3K79) methylation correlates with gene activation (20) and suppression (21). Following this line, AF9-DOT1L complexes mediate transcriptional activation through increased levels of dimethylated H3K79 (13), but are also capable of transcriptional repression through hypermethyla...

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NMDA receptors and schizophrenia

Cited by 211 publications

References 82 publications

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

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