Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

Steullet, Pascal; Cabungcal, Jan-Harry; Kulak, Anita; Kraftsik, Rudolf; Chen, Ying; Dalton, Timothy P.; Cuénod, Michel; Q., Kim

doi:10.1523/jneurosci.3857-09.2010

Cited by 186 publications

(191 citation statements)

References 66 publications

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“…173,[178][179][180] Enhanced ROS generation combined with alterations of antioxidative mechanisms may finally cause higher levels of oxidative stress in fast-spiking interneurons as compared with other neuron subtypes, with devastating consequences on nuclear and mitochondrial DNA and/or functional proteins such as enzymes and ion channels. 173,[181][182][183][184] These putative pathophysiological mechanisms in fast-spiking interneurons, i.e., higher susceptibility to metabolic and oxidative stress, might apply to several neurologic and psychiatric disorders that go along with chronic mitochondrial dysfunction and/or chronic cerebral hypoperfusion (Figure 3). Clinical examples are mitochondrial disorders (mitochondriopathies), arteriosclerosis, ageing, Alzheimer's disease, Parkinson's disease, and schizophrenia.…”

Section: Perspective: Metabolic and Oxidative Stress In Fast-spiking mentioning

confidence: 99%

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Kann

Papageorgiou

Draguhn

2014

J Cereb Blood Flow Metab

236

235

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Gamma oscillations (B30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and g-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

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Section: Perspective: Metabolic and Oxidative Stress In Fast-spiking mentioning

confidence: 99%

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Kann

Papageorgiou

Draguhn

2014

J Cereb Blood Flow Metab

236

235

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“…20 These data prompted the investigation of GCLM knockout mice (GCLM-KO) as a model of schizophrenia. In developing and adult animals, brain GSH levels are decreased by 70%, 29 and GCLM-KO mice show signs of oxidative stress in discrete brain regions, 29,30 including the anterior cingulate cortex. 30 These mice present behavioral alterations such as impaired sensory gating, abnormal response to environmental novelty, and abnormal social and emotion-related behaviors, 31 all known as hallmarks of the disease.…”

Section: Introductionmentioning

confidence: 99%

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

et al. 2014

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Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

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“…36), the rate-limiting enzyme of GSH synthesis. These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22). We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.…”

mentioning

confidence: 99%

Perineuronal nets protect fast-spiking interneurons against oxidative stress

Cabungcal

Steullet

Morishita

et al. 2013

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

437

391

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A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) constitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1, 2). To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons. Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3). For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4, 5). Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8). Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9-11). ...

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Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

Cited by 186 publications

References 66 publications

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Perineuronal nets protect fast-spiking interneurons against oxidative stress

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