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

Kann, Oliver; Papageorgiou, Ismini; Draguhn, Andreas

doi:10.1038/jcbfm.2014.104

Cited by 236 publications

(253 citation statements)

References 187 publications

(450 reference statements)

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“…TLR4 and/or IFN-γ receptor activation also up-regulate NADPH oxidase, which generates superoxide anions (20,52). Superoxide anions can rapidly oxidize NO, resulting in highly toxic peroxynitrite (27). Thus, iNOS and NADPH oxidase in microglia are strong candidates for the mechanism that induces inflammatory neurodegeneration (14,34,44,52).…”

Section: Discussionmentioning

confidence: 99%

“…The increased neuronal excitability in hippocampal slices might be caused by enhanced trafficking of postsynaptic AMPA receptors as mediated by TNF-α (45) and/or the higher incidence of excitatory postsynaptic currents in pyramidal cells as mediated by complex neuron-glia interactions during LPS application (26). Alternatively, enhanced NO release as induced by LPS or IFN-γ might primarily interfere with the specialized function of inhibitory interneurons (27,39).…”

Section: Discussionmentioning

confidence: 99%

“…Gamma oscillations are a common mode of complex cortical information processing in vivo and require precise synaptic communication of excitatory pyramidal cells and inhibitory interneurons (27). Gamma oscillations also provide a sensitive readout for local network (dys)function because they are exquisitely susceptible to structural and metabolic alterations, particularly in fast-spiking, parvalbumin-positive GABAergic interneurons that exert fast rhythmic inhibition on pyramidal cells (27). Notably, persistent gamma oscillations were still present in slice cultures exposed to LPS or IFN-γ (Fig.…”

Section: Lps or Ifn-γ Alone Induces Reactive Phenotypes In Microglia mentioning

confidence: 99%

“…This aspect is highly relevant for several neurologic and psychiatric disorders. Moreover, concomitant alterations in neuronal information processing (i.e., dysfunction in excitatory pyramidal cells and inhibitory GABAergic interneurons, including astrocytes) have been little explored (25)(26)(27).…”

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confidence: 99%

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TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

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

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Microglia (tissue-resident macrophages) represent the main cell type of the innate immune system in the CNS; however, the mechanisms that control the activation of microglia are widely unknown. We systematically explored microglial activation and functional microglia-neuron interactions in organotypic hippocampal slice cultures, i.e., postnatal cortical tissue that lacks adaptive immunity. We applied electrophysiological recordings of local field potential and extracellular K + concentration, immunohistochemistry, design-based stereology, morphometry, Sholl analysis, and biochemical analyses. We show that chronic activation with either bacterial lipopolysaccharide through Toll-like receptor 4 (TLR4) or leukocyte cytokine IFN-γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, CD11b and CD68 up-regulation, and proinflammatory cytokine (IL-1β, TNF-α, IL-6) and nitric oxide (NO) release. Notably, these reactive phenotypes only moderately alter intrinsic neuronal excitability and gamma oscillations (30-100 Hz), which emerge from precise synaptic communication of glutamatergic pyramidal cells and fast-spiking, parvalbumin-positive GABAergic interneurons, in local hippocampal networks. Short-term synaptic plasticity and extracellular potassium homeostasis during neural excitation, also reflecting astrocyte function, are unaffected. In contrast, the coactivation of TLR4 and IFN-γ receptors results in neuronal dysfunction and death, caused mainly by enhanced microglial inducible nitric oxide synthase (iNOS) expression and NO release, because iNOS inhibition is neuroprotective. Thus, activation of TLR4 in microglia in situ requires concomitant IFN-γ receptor signaling from peripheral immune cells, such as T helper type 1 and natural killer cells, to unleash neurotoxicity and inflammation-induced neurodegeneration. Our findings provide crucial mechanistic insight into the complex process of microglia activation, with relevance to several neurologic and psychiatric disorders.hippocampus | microglia | neuronal activity | slice culture | Toll-like receptor

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Lps or Ifn-γ Alone Induces Reactive Phenotypes In Microglia mentioning

confidence: 99%

mentioning

confidence: 99%

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TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

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

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167

150

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“…13 This concept is referred to as temporal binding, and its instrumental phase-coupling appears to be mediated by long-range interneurons. 44 In autism, abnormalities in gamma power, along with established changes in interneuron integrity, may ultimately underlie abnormal stimulus processing. Given the structural and functional abnormalities noted above, temporalbinding deficits, which have been proposed to characterize autism, 16 likely involve socioemotional networks.…”

Section: Electrophysiological Disturbancesmentioning

confidence: 99%

Deep brain stimulation for severe autism: from pathophysiology to procedure

Sinha

McGovern

Sheth

2015

FOC

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Autism is a heterogeneous neurodevelopmental disorder characterized by early-onset impairment in social interaction and communication and by repetitive, restricted behaviors and interests. Because the degree of impairment may vary, a spectrum of clinical manifestations exists. Severe autism is characterized by complete lack of language development and potentially life-threatening self-injurious behavior, the latter of which may be refractory to medical therapy and devastating for affected individuals and their caretakers. New treatment strategies are therefore needed. Here, the authors propose deep brain stimulation (DBS) of the basolateral nucleus of the amygdala (BLA) as a therapeutic intervention to treat severe autism. The authors review recent developments in the understanding of the pathophysiology of autism. Specifically, they describe the genetic and environmental alterations that affect neurodevelopment. The authors also highlight the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development, which create a pattern of dysfunctional neural networks involved in socioemotional processing. They then discuss how these findings implicate the BLA as a key node in the pathophysiology of autism and review a reported case of BLA DBS for treatment of severe autism. Much progress has been made in recent years in understanding the pathophysiology of autism. The BLA represents a logical neurosurgical target for treating severe autism. Further study is needed that considers mechanistic and operative challenges.

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High‐frequency oscillations mirror severity of human temporal lobe seizures

Schönberger

Birk

Lachner-Piza

et al. 2019

Ann Clin Transl Neurol

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ObjectiveMany patients with epilepsy have both focal and bilateral tonic‐clonic seizures (BTCSs), but it is largely unclear why ictal activity spreads only sometimes. Previous work indicates that interictal high‐frequency oscillations (HFOs), traditionally subdivided into ripples (80–250 Hz) and fast ripples (250–500 Hz), are a promising biomarker of epileptogenicity. We aimed to investigate whether HFOs correlate with the emergence of seizure activity and whether they differ between focal seizures (FSs) with impaired awareness and BTCSs.MethodsWe retrospectively analyzed 15 FSs and 13 BTCSs from seven patients with mesial temporal lobe epilepsy, each of them with at least one BTCS and at least one FS. Representative intervals of intracranial electroencephalography from the seizure onset zone (SOZ) and remote non‐SOZ areas were selected to compare pre‐ictal, complex focal, tonic‐clonic, and postictal periods. Ripples and fast ripples were visually identified and their density, that is, percentage of time occupied by the respective events, computed.ResultsRipple and fast ripple densities increased inside the SOZ after seizure onset (P < 0.01) and in remote areas after progression to BTCSs (P < 0.01). Postictal SOZ ripple density dropped below pre‐ictal levels (P < 0.001). Prior to onset of bilateral tonic‐clonic movements, ripple density inside the SOZ is higher in BTCSs than in FSs (P < 0.05).InterpretationRipples and fast ripples correlate with onset and spread of ictal activity. Abundant ripples inside the SOZ may reflect the activation of specific neuronal networks related to imminent spread of seizure activity.

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

Cited by 236 publications

References 187 publications

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Deep brain stimulation for severe autism: from pathophysiology to procedure

High‐frequency oscillations mirror severity of human temporal lobe seizures

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