Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia

Stefani, Mark R.; Moghaddam, Bita

doi:10.1016/j.biopsych.2004.11.031

Cited by 141 publications

(112 citation statements)

References 25 publications

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“…This laboratory has demonstrated that administration of PCP on P7, 9, and 11 is associated with deficits in pre-pulse inhibition as well as in short-term working memory (Wang et al, 2001;Wiley et al, 2003). Recent studies from other laboratories have also reported that transient NMDAR blockade during brain development caused behavioral, structural, and molecular abnormalities in adulthood (Harris et al, 2003;Stefani and Moghaddam, 2005). Additional validation of this model comes from a comparison of PCP-induced neurotoxicity and postmortem schizophrenic brains.…”

Section: Discussionmentioning

confidence: 95%

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

Wang

Johnson

2006

Neuropsychopharmacol

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This study determined the role of caspase-3 in phencyclidine (PCP)-induced neurodegeneration in postnatal rats. PCP administration to postnatal day 7 rats induced a dose-dependent increase in caspase-3 enzymatic activity in frontal cortex, striatum, and hippocampus. Enzymatic activation was present at 4 h, peaked between 6 and 12 h, and disappeared by 24 h. Further, cleaved caspase-3-immunoreactive neurons were detected as early as 2 h in the cortex, and were found throughout the brain, including, in addition, the thalamus and striatum. Within the cingulate, frontal, parietal, and retrosplenial cortices, immunoreactivity was specific for layers II-IV (especially layer II). Neurons positive for both silver staining and terminal deoxynucleotidyl transferase biotin-d-UTP nick-end labeling (TUNEL) were found in the same brain regions and subregions. Double labeling experiments confirmed that cleaved caspase-3 and TUNEL were coexpressed in many neurons in all brain regions and subregions studied. Temporal studies revealed that procaspase-3 cleavage preceded TUNEL staining by about 3 h, with many neurons being positive for both caspase-3 and TUNEL 9 h after PCP treatment. In organotypic corticostriatal slices, PCP caused a concentration-and time-dependent cleavage of procaspase-3 that was also colocalized with TUNEL staining in layers II-IV of the parietal cortex. Caspase-3 activation again preceded PCP-induced DNA damage assessed by TUNEL. PCP-induced neuronal death in vitro as measured by TUNEL staining was blocked 85% by Ac-AAVALLPAVLLALLAPDEVD-CHO, a cell-permeable selective caspase-3 inhibitor. These data demonstrate that caspase-3 activation plays a necessary role in the regionally selective neuronal death induced by PCP in the developing rat brain.

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Section: Discussionmentioning

confidence: 95%

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

Wang

Johnson

2006

Neuropsychopharmacol

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“…In contrast to the reversible effects observed in adult animals , embryonic and repetitive exposures during the second postnatal week to NMDA-R antagonists can produce loss of PV-interneurons and persistent behavioral and neurochemical deficits that appear only in adulthood (Stefani and Moghaddam, 2005a;Mouri et al, 2007;. Mice expressing 10% of the normal NMDA-R activity develop cognitive disruptions resembling those found in schizophrenia (reviewed in (Gainetdinov et al, 2001)).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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“…1 NMDA receptors also play a role in neuronal development and a transgenic mouse line, which has reduced expression of the NR1 subunit, has schizophrenic like behaviours. 11,12 Recent advances in psychiatric genetics have identified an increasing number of schizophrenia risk genes including Disrupted in Schizophrenia 1 (DISC1), neuregulin-1 (NRG1) and dysbindin (DTNBP1). 2 Disruption of the DISC1 gene by a balanced (1;11) (q42;q14) translocation was originally reported to co-segregate with major psychiatric illnesses in a Scottish family.…”

Section: Introductionmentioning

confidence: 99%

Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia

et al. 2006

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Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cellcycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.

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Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia

Cited by 141 publications

References 25 publications

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia

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