Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex

Zhang, Yuchun; Behrens, M. Margarita; Lisman, John

doi:10.1152/jn.00079.2008

Cited by 99 publications

(105 citation statements)

References 42 publications

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“…In vitro studies initially described reduced gamma by ketamine (Cunningham et al, 2006;Zhang et al, 2008), although subsequent studies have refined this description by suggesting a regionally specific ketamine effect such that ketamine increases gamma at the primary auditory cortex but reduces or has no effect in other brain regions (Roopun et al, 2008). Therefore, the observed gamma augmentation at D4 (40-85 Hz) is consistent with prior observations.…”

Section: Discussionsupporting

confidence: 75%

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Hong

Summerfelt

Boyer

et al. 2009

Neuropsychopharmacol

253

151

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Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p ¼ 0.006) and reduced lowfrequency oscillations (delta band at 1-5 Hz, po0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p ¼ 0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

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Section: Discussionsupporting

confidence: 75%

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Hong

Summerfelt

Boyer

et al. 2009

Neuropsychopharmacol

253

151

View full text Add to dashboard Cite

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“…Similar exposures to ketamine in rats lead to an enduring decrease of inhibitory tone in prefrontal cortex (Zhang et al, 2008), supporting the idea that repetitive exposures to NMDA-R antagonists produce enduring effects resembling those observed in schizophrenia.…”

Section: The Role Of Superoxide In the Persistent Effects Of Nmda-r Asupporting

confidence: 60%

“…The pro-psychotic effects of NMDA-R antagonists appear only in early adulthood and exposure of four week old rats to ketamine on two consecutive days did not reduce GAD67 immunoreactivity (Zhang et al, 2008). However, 24 h continuous exposure of three week old cultured neurons to ketamine produces a substantial reduction in GAD67 immunoreactivity (Kinney et al, 2006).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 91%

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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“…Also, these findings exclude a role for disrupted glutamate release in the development of such circuit abnormalities. Indeed, several models suggest disruption of excitatory input into inhibitory neurons as a cause of reduced PV immunoreactivity (60)(61)(62). The shared association between PV cell disruption and the described auditory phenotypes in schizophrenia as well as the Dys1 −/− mice indicates that understanding the mechanisms leading to PV dysregulation may be critical to understanding the development of schizophrenia-associated endophenotypes.…”

Section: Discussionmentioning

confidence: 99%

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Carlson

Talbot²,

Halene³

et al. 2011

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

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DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.GABAergic | γ-oscillation | hippocampus | evoked response spectral perturbation | Sandy mouse P atients with schizophrenia have reduced amplitude and gating of auditory event-related potentials (ERPs) (1, 2). Recent clinical studies also show abnormal γ-band oscillations (30-100 Hz) as an endophenotype of the illness that is associated with reduced cognitive function (3-7). Work in animal models shows a prominent role of cortical inhibitory networks in generating γ-oscillations (8, 9), which in turn, supports the role of aberrant GABAergic inhibition as an important potential component of schizophrenia (4,7,10,11). The GABA-producing enzyme glutamic acid decarboxylase is dysregulated in schizophrenia, and postsynaptic GABA A receptors are dysregulated as well (4). Risk alleles for GABA A receptor subunits are also associated with the disease (12, 13), although linkage is weaker than the linkage found with dysbindin-1 and other candidate genes such as DISC1 (14). At the anatomical level, there is a loss of immunoreactivity for parvalbumin (PV) in schizophrenia. PV is a calcium-binding protein marker for a class of fast-spiking GABAergic neurons. It is debated whether reduced PV in postmortem studies is caused by reduction in cell number or merely loss of protein expression. In either case, reduced PV immunoreactivity suggests disruption of an important source of local circuit inhibition (4, 15).Although clinical electrophysiological and postmortem anatomical findings support the role of GABA dysfunction in schizophrenia, a larger set of schizophrenia risk haplotypes are thought to confer reduced NMDA receptor-mediated function and changes in glutamatergic transmission [e.g., DISC1; Neuregu...

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Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex

Cited by 99 publications

References 42 publications

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

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

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

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