Novel Environment and GABA Agonists Alter Event-Related Potentials in <i>N</i>-Methyl-d-aspartate NR1 Hypomorphic and Wild-Type Mice

Bodarky, Christina L.; Halene, Tobias B.; Ehrlichman, Richard S.; Banerjee, Anamika; Ray, Radharaman; Hahn, Chang-Gyu; Jonak, G J; Siegel, Steven J.

doi:10.1124/jpet.109.150938

Cited by 14 publications

(13 citation statements)

References 39 publications

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“…The electrode pedestal was secured to the skull with ethyl cyanoacrylate (Loctite; Henkel) and dental cement (Ortho Jet; Lang Dental). This recording paradigm can replicate clinical auditory ERP findings in humans that are primarily sourced to the cortex (11,21,41,70,(74)(75)(76).…”

Section: Methodsmentioning

confidence: 79%

“…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).…”

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confidence: 99%

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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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Section: Methodsmentioning

confidence: 79%

mentioning

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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“…Global NR1 hypomorphic mice did not completely reproduce the alterations of auditory ERPs in schizophrenia, though they exhibited a number of behavioral deficits relevant to the disease (22). Interestingly, however, mice lacking NMDARs specifically in PV + neurons showed electrophysiological phenotypes consistent with schizophrenia (18,29,113), which essentially included a raised baseline gamma-power and reduced gamma-activity evoked or induced by sensory inputs.…”

Section: Nox2 In Schizophreniamentioning

confidence: 98%

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

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Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

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“…Since then, NR1 hypomorphic mice have been considered as a translation model for the disease. Measure of auditory and visual event related potentials showed significant increased amplitudes of P20 and N40 in NR1 hypomorphic mice, suggesting decreased inhibitory tone (Bodarky et al, 2009). Indeed, auditory gating for the P20 and the N40 peak is significantly impaired in these mice compared to their wild-type littermates (Bickel et al, 2007(Bickel et al, , 2008.…”

Section: Dopamine Comt Tg Micementioning

confidence: 99%

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms

Jutzeler¹,

McMullen²,

Featherstone³

et al. 2011

Psychiatric Disorders - Trends and Developments

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Novel Environment and GABA Agonists Alter Event-Related Potentials in N-Methyl-d-aspartate NR1 Hypomorphic and Wild-Type Mice

Cited by 14 publications

References 39 publications

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

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

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms

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