A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities

Rujescu, Dan; Bender, Andreas; Keck, Martin E.; Hartmann, Annette M.; Ohl, Frauke; Ræder, Hanna; Giegling, Ina; Genius, Just; McCarley, Robert W.; Möller, Hans‐Jürgen; Grunze, Heinz

doi:10.1016/j.biopsych.2005.08.029

Cited by 221 publications

(153 citation statements)

References 61 publications

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“…Our laboratory has advanced the hypothesis of a cortical circuit abnormality (deficient recurrent inhibition as a result of γ-aminobutyric acid [GABA]-ergic abnormalities) as a mechanism (56). This hypothesis is supported by preclinical work (57,58), gamma oscillations in schizophrenia (59), and postmortem work (60). In our model, dendritic remodeling and regression occurs as a result of increased excitatory input due to decreased GABAergic recurrent inhibition, which, in turn, results from hypofunction of the recurrent collateral N-methyl-D-aspartate receptor on GABAergic interneurons (61).…”

Section: Longitudinal Volume Changes In Fe Schizophreniamentioning

confidence: 91%

Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study

Nakamura

Salisbury

Hirayasu

et al. 2007

Biological Psychiatry

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149

121

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Section: Longitudinal Volume Changes In Fe Schizophreniamentioning

confidence: 91%

Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study

Nakamura

Salisbury

Hirayasu

et al. 2007

Biological Psychiatry

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149

121

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“…Furthermore, while the behavioral and neurochemical effects of acute exposures to NMDA-R antagonists are believed to occur upon disinhibition of cortical excitatory activity due to increased sensitivity of inhibitory systems to blockade of NMDA-R function (Olney et al, 1999;Homayoun and Moghaddam, 2007;Lisman et al, 2008;Middleton et al, 2008), they do not lead to the enduring changes in PV-interneurons observed in schizophrenia. Repetitive exposures to NMDA-R antagonists, on the other hand, produce a reduction in GAD67 expression in PVinterneurons of rodents (Behrens et al, 2007 as well as decreased expression of parvalbumin in rodents and non-human primates (Cochran et al, 2002;Keilhoff et al, 2004;Rujescu et al, 2006;Morrow et al, 2007).…”

Section: Introductionmentioning

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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“…NMDAR antagonists generally act at the functional level of the synapse [11,13], although there is some evidence for downstream transcription effects [16,24]. In the current experiment, we predicted that disrupted mate preference responses would be reflected in gene modules linked to dynamic preference behaviours if blocked glutamatergic signalling altered normal female responses to males.…”

Section: Discussionmentioning

confidence: 81%

Testing synaptic plasticity in dynamic mate choice decisions: N -methyl d -aspartate receptor blockade disrupts female preference

Ramsey

Cummings

2014

Proc. R. Soc. B.

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Social behaviours such as mate choice require context-specific responses, often with evolutionary consequences. Increasing evidence indicates that the behavioural plasticity associated with mate choice involves learning. For example, poeciliids show age-dependent changes in female preference functions and express synaptic-plasticity-associated molecular markers during mate choice. Here, we test whether social cognition is necessary for female preference behaviour by blocking the central player in synaptic plasticity, NMDAR (N-methyl D-aspartate receptor), in a poeciliid fish, Xiphophorus nigrensis. After subchronic exposure to NMDAR antagonist MK-801, female preference behaviours towards males were dramatically reduced. Overall activity levels were unaffected, but there was a directional shift from 'social' behaviours towards neutral activity. Multivariate gene expression patterns significantly discriminated between females with normal versus disrupted plasticity processes and correlated with preference behaviours-not general activity. Furthermore, molecular patterns support a distinction between 'preference' (e.g. neuroserpin, neuroligin-3, NMDAR) and 'sociality' (isotocin and vasotocin) gene clusters, highlighting a possible conservation between NMDAR disruption and nonapeptides in modulating behaviour. Our results suggest that mate preference may involve greater social memory processing than overall sociality, and that poeciliid preference functions integrate synaptic-plasticity-oriented 'preference' pathways with overall sociality to invoke dynamic, context-specific responses towards favoured males and away from unfavoured males.

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A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities

Cited by 221 publications

References 61 publications

Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study

Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study

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

Testing synaptic plasticity in dynamic mate choice decisions: N -methyl d -aspartate receptor blockade disrupts female preference

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