Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

Elzoheiry, Shehabeldin; Lewen, Andrea; Schneider, Justus; Both, Martin; Hefter, Dimitri; Boffi, Juan Carlos; Hollnagel, Jan‐Oliver

doi:10.1177/0271678x19892657

Cited by 13 publications

(16 citation statements)

References 234 publications

(507 reference statements)

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“…The vulnerability of PV+ FSI is a particularly important issue, and it is presently unclear to which extent their altered function contributes to impaired post-hypoxic network activity (Johansen et al, 1983;Nitsch et al, 1989;Moga et al, 2002;Wang, 2003;Elzoheiry et al, 2019;Povysheva et al, 2019). Earlier studies found unchanged numbers of PV-IN in contrast to reduced CA1 pyramidal cell numbers several days after HI in vivo (Johansen et al, 1983;Nitsch et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…Calciumbinding properties of parvalbumin are discussed to reduce neurotoxic effects of calcium overload during HI (Tortosa and Ferrer, 1993). However, more recent studies indicate impaired function of inhibitory neurons compared to excitatory neurons after transient metabolic insults (Moga et al, 2002;Wang, 2003;Elzoheiry et al, 2019;Povysheva et al, 2019). It is important to note the methodical differences in those studies in terms of insult severity and outcome measures (histological cell death versus electrophysiological function).…”

Section: Discussionmentioning

confidence: 99%

“…Of particular importance for such fast synchronization processes are fast-spiking parvalbumin+ interneurons (PV-IN) (Ylinen et al, 1995). Importantly, these cells might be especially vulnerable to HI-induced functional loss and cell damage (Kann et al, 2014;Kann, 2016;Elzoheiry et al, 2019;Povysheva et al, 2019). At the network level, this may lead to decreased inhibition-excitation ratio, disturbed activity patterns and altered coupling between cellular spikes and local field potential (LFP) oscillations.…”

Section: Introductionmentioning

confidence: 99%

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Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

Grube

Heuermann

Rozov

et al. 2021

eNeuro

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Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic attacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYR) and interneurons. We therefore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSI) after hypoxicischemic insults. Transient oxygen-glucose deprivation (OGD) in ex vivo hippocampal slices led to a rapid loss of neuronal activity and spontaneous network oscillations (sharp wave-ripple complexes, SPW-R), and to the occurrence of a spreading depolarization. Following reperfusion, both SPW-R and neuronal spiking resumed, but FSI activity remained strongly reduced compared to PYR. Whole-cell recordings in CA1 PYR revealed, however, a similar reduction of both excitatory and inhibitory postsynaptic currents, leaving inhibition-excitation balance unaltered. At the network level, SPW-R incidence was strongly reduced and the remaining network events showed region-specific changes including reduced ripple energy in CA3 and increased ripple frequency in CA1.Together, our data show that transient hippocampal energy depletion results in severe functional alterations at the cellular and network level. While inhibition-excitation balance is maintained, synaptic activity, interneuron spiking and coordinated network patterns remain reduced. Such alterations may be network-level correlates of cognitive and functional deficits after cerebral HI. 3 Significance statementNeurons can recover following transient hypoxia-ischemia (HI), which is crucial for the survival of brain tissue in the ischemic penumbra. Brain tissue recovered from stroke is characterized by aberrant network activity. Essential to fast network oscillations are fast-spiking interneurons (FSI), which, due to their high energy demand, might be especially vulnerable to metabolic stress. Here, our data from murine hippocampal slices demonstrate impaired functional recovery of FSI after transient HI compared to pyramidal cells. Concurrently, ripple oscillations re-emerge with reduced incidence and altered waveforms. Thus, the present study confirms increased functional vulnerability of hippocampal FSI to HI and reveals specific impairments of network activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

Grube

Heuermann

Rozov

et al. 2021

eNeuro

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“…Thus, [K + ] o rarely exceeds 0.5 mM from a baseline of 3.0 mM during gamma oscillations reflecting the maintenance of K + homeostasis (Kann et al., 2011, 2016; Somjen, 2002), which differs from the larger [K + ] o transients induced by artificial repetitive electrical stimulation in situ and in vivo (Heinemann & Lux, 1977; Kann et al., 2003; Liotta et al., 2012). Conversely, gamma oscillations are exquisitely sensitive to metabolic and oxidative stress (Elzoheiry et al., 2019; Huchzermeyer et al., 2008; Papageorgiou et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue

Lewen

Cesetti

et al. 2020

J of Neuroscience Research

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Microglial cells (resident macrophages) feature rapid activation in CNS disease and can acquire multiple phenotypes exerting neuroprotection or neurotoxicity. The functional impact of surveying (“resting”) microglia on neural excitability and neurotransmission in physiology is widely unknown, however. We addressed this issue in male rat hippocampal slice cultures (in situ) by pharmacological microglial ablation within days and by characterizing neuronal gamma‐band oscillations (30–70 Hz) that are highly sensitive to neuromodulators and disturbances in ion and energy regulation. Gamma oscillations support action potential timing and synaptic plasticity, associate with higher brain functions like perception and memory, and require precise communication between excitatory pyramidal cells and inhibitory (GABAergic) interneurons. The slice cultures featured well‐preserved hippocampal cytoarchitecture and parvalbumin‐positive interneuron networks, microglia with ramified morphology, and low basal levels of IL‐6, TNF‐α, and nitric oxide (NO). Stimulation of slice cultures with the pro‐inflammatory cytokine IFN‐γ or bacterial LPS serving as positive controls for microglial reactivity induced MHC‐II expression and increased cytokine and NO release. Chronic exposure of slice cultures to liposome‐encapsulated clodronate reduced the microglial cell population by about 96%, whereas neuronal structures, astrocyte GFAP expression, and basal levels of cytokines and NO were unchanged. Notably, the properties of gamma oscillations reflecting frequency, number and synchronization of synapse activity were regular after microglial depletion. Also, electrical stimulus‐induced transients of the extracellular potassium concentration ([K+]o) reflecting cellular K+ efflux, clearance and buffering were unchanged. This suggests that nonreactive microglia are dispensable for neuronal homeostasis and neuromodulation underlying network signaling and rhythm generation in cortical tissue.

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“…We investigated the effects of GM-CSF on microglianeuron interactions in organotypic hippocampal slice cultures of the rat, which feature well-preserved cytoarchitecture and functional neuronal networks (Figs. 2 and 3) [30,32,37,44]. Slice cultures inherently lack leukocyte infiltration during experimental exposures and thus permit to explore the reactivity of microglia in the absence of invading granulocytes, monocytes, and lymphocytes [22][23][24].…”

Section: Exploring Microglia-neuron Interactions In Situmentioning

confidence: 99%

GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ

Dikmen

Hemmerich

Lewen

et al. 2020

J Neuroinflammation

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Background: The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30-70 Hz). Gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and they are exquisitely sensitive to metabolic and oxidative stress. Methods: We explored the effects of chronic GM-CSF exposure (72 h) on microglia in male rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortex tissue lacking leukocyte invasion (adaptive immunity). We applied extracellular electrophysiological recordings of local field potential, immunohistochemistry, design-based stereology, biochemical analysis, and pharmacological ablation of microglia. Results: GM-CSF triggered substantial proliferation of microglia (microgliosis). By contrast, the release of proinflammatory cytokines (IL-6, TNF-α) and nitric oxide, the hippocampal cytoarchitecture as well as the morphology of parvalbumin-positive inhibitory interneurons were unaffected. Notably, GM-CSF induced concentration-dependent, long-lasting disturbances of gamma oscillations, such as slowing (beta frequency band) and neural burst firing (hyperexcitability), which were not mimicked by the T lymphocyte cytokine IL-17. These disturbances were attenuated by depletion of the microglial cell population with liposome-encapsulated clodronate. In contrast to priming with the cytokine IFN-γ (type II interferon), GM-CSF did not cause inflammatory neurodegeneration when paired with the TLR4 ligand LPS.

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Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

Cited by 13 publications

References 234 publications

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue

GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ

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