PCP: from pharmacology to modelling schizophrenia

Morris, Brian J.; Cochran, S.; Pratt, Judith A.

doi:10.1016/j.coph.2004.08.008

Cited by 287 publications

(168 citation statements)

References 58 publications

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“…We show that the part of the STDP curve which represents LTD is shorter in the presence of feedback inhibition. This result is a possible explanation for the observed depression in the prefrontal cortex after chronic application of the NMDA receptor antagonists which is a recent model for schizophrenia (Morris et al, 2005). Our model predicts that chronic Phencyclidine (PCP) treatment widens the time window for LTD and consequently causes more LTD in the cortical micro-circuitry.…”

Section: Introductionmentioning

confidence: 63%

“…There are two main hypotheses which link reduced interneu-ron activity to schizophrenia: one states that NMDA hypofunction in cortical interneurons is responsible for less interneuron activity (Morris et al, 2005) and the other states that there is less GABA released from the interneuron through a hypofunction of the GABA synthesizing enzyme GAD67 (Guidotti et al, 2005). In order to find out which of these hypotheses is more likely to be the cause of schizophrenia we have simulated both cases in realistic GENESIS simulations involving one pyramidal and one perisomatic inhibitory neuron.…”

Section: Introductionmentioning

confidence: 99%

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How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

et al. 2011

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It has been shown that plasticity is not a fixed property but, in fact, changes depending on the location of the synapse on the neuron and/or changes of biophysical parameters. Here we investigate how plasticity is shaped by feedback inhibition in a cortical microcircuit. We use a differential Hebbian learning rule to model spike-timing dependent plasticity and show analytically that the feedback inhibition shortens the time window for LTD during spike-timing dependent plasticity but not for LTP. We then use a realistic GENESIS model to test two hypothesis about interneuron hypofunction and conclude that a reduction in GAD67 is the most likely candidate as the cause for hypofrontality as observed in Schizophrenia.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

et al. 2011

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“…41 With regard to PPI, specifically, the findings in healthy patients are mixed, with one study reporting disruption of 'PPI-like' auditory gating following treatment with ketamine, 42 some studies reporting no effects of ketamine on PPI, 43,44 and others reporting enhancement of PPI. [45][46][47] However, it is clear that patients with schizophrenia do have altered PPI 1,5,[48][49][50] and that in nonhuman primates 51,52 and rodents, [53][54][55][56] treatment with NMDA antagonists disrupts PPI.…”

Section: Discussionmentioning

confidence: 99%

Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice

2008

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It has been previously suggested that oxytocin (Oxt) may act as a natural antipsychotic. To test this hypothesis, we investigated whether disruption of the oxytocin gene (OxtÀ/À) made mice more susceptible to the psychosis-related effects of amphetamine (Amp), apomorphine (Apo) and phencyclidine (PCP). We examined drug-induced changes in the prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating deficits characteristic of several psychiatric and neurological disorders, including schizophrenia. We found that treatment with Amp, Apo and PCP all had effects on PPI. However, in OxtÀ/À mice, but not Oxt þ / þ mice, PCP treatment resulted in large PPI deficits. As PCP is a noncompetitive N-methyl-D-aspartic acid receptor antagonist, these findings suggest that the absence of Oxt alters the glutamatergic component of the PPI.

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“…Repetitive NMDA-R antagonist treatment in animals produce more persistent effects on stereotypy and locomotor activity, as well as enduring cognitive deficits and neurochemical changes that resemble more accurately the alterations observed in schizophrenia (Jentsch and Roth, 1999;Morris et al, 2005;Mouri et al, 2007). For example, the initial hypermetabolism, observed after acute NMDA-R antagonist exposure, is followed by a decrease in metabolic activity in the PFC, as well as within structures of the auditory system, and the reticular nucleus of the thalamus (Cochran et al, 2003).…”

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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PCP: from pharmacology to modelling schizophrenia

Cited by 287 publications

References 58 publications

How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice

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

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