Neuroprotective function for ramified microglia in hippocampal excitotoxicity

Vinet, Jonathan; Weering, Hilmar R. J. van; Heinrich, Annette; Kälin, Roland E.; Wegner, Anja; Brouwer, Nieske; Heppner, Frank L.; Rooijen, Nico van; Boddeke, Hendrikus; Biber, Knut

doi:10.1186/1742-2094-9-27

Cited by 237 publications

(245 citation statements)

References 69 publications

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“…2 C and D). These experiments demonstrate that slice cultures are a reliable model for effective tissue exposure and induction of diverse reactive microglial phenotypes (33,34).…”

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

confidence: 73%

“…The morphology of dendrites (MAP2 staining) and GABAergic interneurons (parvalbumin staining) that are exquisitely susceptible to metabolic and oxidative stress (27) was well preserved. As a positive control, slice cultures were exposed to glutamate receptor agonists N-methyl-D-aspartate (NMDA; 5 μM) and kainic acid (KA; 5 μM) to induce excitotoxicity (32,33). NMDA+KA resulted in massive neuronal death ( Fig.…”

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

167

150

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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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“…2 C and D). These experiments demonstrate that slice cultures are a reliable model for effective tissue exposure and induction of diverse reactive microglial phenotypes (33,34).…”

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

confidence: 73%

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

confidence: 99%

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.

167

150

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“…A report by Kim et al [60] showed reduced neurogenesis with minocycline treatment. The depletion and replenishment of microglia were respectively augmented and reduced by N-methyl-D-aspartate-or oxygen glucose deprivation-induced neuronal cell death [61,62]. Faustino et al [63] also reported that microglia depletion enhances inflammation and injury in acute neonatal focal stroke.…”

Section: Microgliamentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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“…It has long been thought that ramified microglia were “resting” in the healthy brain, however, evidence suggests that microglial cells are highly active in their presumed resting state, continually screening their microenvironment with extremely motile processes and protrusions (Nimmerjahn, Kirchhoff, & Helmchen, 2005). Moreover, it has been shown that ramified microglia not only monitor their microenvironment but also protect hippocampal neurons under pathological conditions (Vinet et al., 2012). Thus, according to the present experimental conditions, these observations suggest that hippocampal organotypic slices present active and neuroprotective ramified microglia.…”

Section: Discussionmentioning

confidence: 99%

A new method allowing long‐term potentiation recordings in hippocampal organotypic slices

2017

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BackgroundHippocampal organotypic slices are used to improve the understanding of synaptic plasticity mechanisms because they allow longer term studies compared to acute slices. However, it is more delicate to keep cultures alive in the recording system outside in vitro conditions. Experiments from the organotypic cultures are common but the handling of slices is rarely described in the literature, even though tissue preservation is crucial. Instruments are sometimes required to extract the slices from the culture inserts but this approach is delicate and can lead to damage, given how strongly the slices are attached to the insert.MethodsA new configuration is proposed to secure the transfer of slices from the incubator to the recording chamber through an adaptor piece that can be designed for any model of chamber and/or insert. The adaptor is a Plexiglas ring in which a culture insert containing the slice can be easily introduced and stabilized. This system allows slices to be placed in the interface for electrophysiological investigations without having to detach them from the insert. That way, no damage is caused and the recording system can safely hold the slices, maintaining them close to culture conditions.ResultsIn addition to the description of the adaptation system, slices were characterized. Their viability was validated and microglial expression was observed. According to the experimental conditions, neuroprotective ramified microgliocytes are present. Dendritic spines studies were also performed to determine neuronal network maturity in culture. Moreover, SKF 83822 hydrobromide and three trains of 100 pulses at 100 Hz with a 10‐min inter‐train interval are suggested to induce long‐term potentiation and to record an increase of fEPSP amplitude and slope.ConclusionThis paper provides detailed information on the preparation and characterization of hippocampal organotypic slices, a new recording configuration more suitable for cultures, and a long‐term potentiation protocol combining SKF and trains.

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Neuroprotective function for ramified microglia in hippocampal excitotoxicity

Cited by 237 publications

References 69 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

Microglia and Monocyte-Derived Macrophages in Stroke

A new method allowing long‐term potentiation recordings in hippocampal organotypic slices

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