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Featured researches published by Andrea Lewen.


The Journal of Physiology | 2003

Hyperpolarizing inhibition develops without trophic support by GABA in cultured rat midbrain neurons

Stefan Titz; Michael Hans; Wolfgang Kelsch; Andrea Lewen; Dieter Swandulla; Ulrich Misgeld

During a limited period of early neuronal development, GABA is depolarizing and elevates [Ca2+]i, which mediates the trophic action of GABA in neuronal maturation. We tested the attractive hypothesis that GABA itself promotes the developmental change of its response from depolarizing to hyperpolarizing ( Ganguly et al. 2001 ). In cultured midbrain neurons we found that the GABA response changed from depolarizing to hyperpolarizing, although GABAA receptors had been blocked throughout development. In immature neurons prolonged exposure of the cells to nanomolar concentrations of GABA or brief repetitive applications of GABA strongly diminished the elevation of [Ca2+]i by GABA. As revealed by gramicidin perforated‐patch recording, reduced [Ca2+]i responses were due to a diminished driving force for Cl−. This suggests that immature neurons do not have an efficient inward transport that can compensate the loss of cytosolic Cl− resulting from sustained GABAA receptor activation by ambient GABA. Transient increases in external K+, which can induce voltage‐dependent Cl− entry, restored GABA‐induced [Ca2+]i elevations. In mature neurons, GABA reduced [Ca2+]i provided that background [Ca2+]i was elevated by the application of an L‐type Ca2+ channel agonist. This was probably due to a hyperpolarization of the membrane by Cl− currents. K+‐Cl− cotransport maintained the gradient for hyperpolarizing Cl− currents. We conclude that in immature midbrain neurons an inward Cl− transport is not effective although the GABA response is depolarizing. Further, GABA itself is not required for the developmental switch of GABAergic responses from depolarizing to hyperpolarizing in cultured midbrain neurons.


Proceedings of the National Academy of Sciences of the United States of America | 2016

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

Ismini E. Papageorgiou; Andrea Lewen; Lukas V. Galow; Tiziana Cesetti; Jörg Scheffel; Tommy Regen; Uwe-Karsten Hanisch; Oliver Kann

Significance Microglia (brain macrophages) become rapidly activated in most neuropsychiatric disorders. A popular concept is that a single pathogenic stimulus, such as bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4), is sufficient to induce a reactive proinflammatory phenotype in microglia that exerts neurotoxicity. This concept is biologically risky, however. Here we provide evidence that chronic activation with either LPS or the leukocyte cytokine IFN-γ induces different reactive phenotypes in microglia of postnatal hippocampal tissue. Notably, these phenotypes only moderately alter diverse neuronal functions. In contrast, coactivation of TLR4 and IFN-γ receptors results in massive neural dysfunction and death. Thus, activation of TLR4 in microglia in situ requires concomitant IFN-γ signaling from other host immune cells to induce neurodegeneration. 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.


The Journal of Physiology | 1997

GABAB receptor‐mediated inhibition of spontaneous inhibitory synaptic currents in rat midbrain culture.

Jutta Rohrbacher; Wolfgang Jarolimek; Andrea Lewen; Ulrich Misgeld

1. Tight‐seal, whole‐cell recording was used to study GABAB receptor‐mediated inhibition of spontaneous inhibitory synaptic currents in cultured rat midbrain neurones. 2. Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were recorded in tetrodotoxin (TTX), Cd2+ and Ba2+. (R)‐(‐)‐baclofen reduced the frequency of mIPSCs through a presynaptic mechanism. The EC50 for this effect was 7 microM. It was antagonized by the GABAB receptor antagonist CGP55845A (0.5 microM). 3. In pertussis toxin (PTX)‐treated cultures, some GABAB receptor‐mediated reduction of the frequency of mIPSCs persisted. In contrast, PTX treatment totally abolished inhibition of miniature excitatory postsynaptic currents (mEPSCs). 4. In PTX‐treated cultures, a saturating concentration of (R)‐(‐)‐baclofen inhibited action potential‐generated IPSCs but no EPSCs. 5. PTX treatment abolished the (R)‐(‐)‐baclofen‐mediated inhibition of high voltage‐activated somatic Ca2+ currents and of spontaneous IPSCs depending on presynaptic Ca2+ entry. 6. We conclude that cellular mechanisms underlying GABAB receptor‐mediated inhibition of mIPSCs contribute to auto‐inhibition of GABA release.


Frontiers in Neuroscience | 2014

Energy substrates that fuel fast neuronal network oscillations

Lukas V. Galow; Justus Schneider; Andrea Lewen; Thuy-Truc Ta; Ismini E. Papageorgiou; Oliver Kann

Fast neuronal network oscillations in the gamma-frequency band (30–−100 Hz) provide a fundamental mechanism of complex neuronal information processing in the hippocampus and neocortex of mammals. Gamma oscillations have been implicated in higher brain functions such as sensory perception, motor activity, and memory formation. The oscillations emerge from precise synapse interactions between excitatory principal neurons such as pyramidal cells and inhibitory GABAergic interneurons, and they are associated with high energy expenditure. However, both energy substrates and metabolic pathways that are capable to power cortical gamma oscillations have been less defined. Here, we investigated the energy sources fueling persistent gamma oscillations in the CA3 subfield of organotypic hippocampal slice cultures of the rat. This preparation permits superior oxygen supply as well as fast application of glucose, glycolytic metabolites or drugs such as glycogen phosphorylase inhibitor during extracellular recordings of the local field potential. Our findings are: (i) gamma oscillations persist in the presence of glucose (10 mmol/L) for greater than 60 min in slice cultures while (ii) lowering glucose levels (2.5 mmol/L) significantly reduces the amplitude of the oscillation. (iii) Gamma oscillations are absent at low concentration of lactate (2 mmol/L). (iv) Gamma oscillations persist at high concentration (20 mmol/L) of either lactate or pyruvate, albeit showing significant reductions in the amplitude. (v) The breakdown of glycogen significantly delays the decay of gamma oscillations during glucose deprivation. However, when glucose is present, the turnover of glycogen is not essential to sustain gamma oscillations. Our study shows that fast neuronal network oscillations can be fueled by different energy-rich substrates, with glucose being most effective.


European Journal of Neuroscience | 2006

Intracellular acidification in neurons induced by ammonium depends on KCC2 function.

Stefan Titz; Sheriar G. Hormuzdi; Andrea Lewen; Hannah Monyer; Ulrich Misgeld

The Cl–‐extruding neuron‐specific K+–Cl– cotransporter KCC2, which establishes hyperpolarizing inhibition, can transport NH4+ instead of K+. It is, however, not clear whether KCC2 provides the only pathway for neuronal NH4+ uptake. We therefore investigated NH4+ uptake in cultured rat brain neurons. In neurons cultured for > 4 weeks, the response to NH4Cl applications (5 mm) consisted of an alkaline shift which reversed to an acid shift within seconds. Rebound acid shifts which followed brief applications of NH4Cl were blocked by furosemide (100 µm). They were rather insensitive to bumetanide (1 and 100 µm), in contrast to those induced in cultured glial cells. Rebound acid shifts persisted in the presence of 1 mm Ba2+ and in Na+‐free solution but were inhibited by extracellular K+. In neurons with depolarizing GABA responses, indicating the absence of functional KCC2, applications of NH4Cl barely induced an acidosis. However, large rebound acid shifts occurred in neurons that had changed their GABA response from Ca2+ increases to Ca2+ decreases. Rebound acid shifts continued to increase even after the change in the GABA response had occurred and could be induced earlier in neurons transfected with KCC2 cDNA. We conclude that KCC2 provides the main pathway for fast neuronal NH4+ uptake. Therefore, NH4Cl‐induced rebound acid shifts can be used to indicate the development of KCC2 function. Further, the well known up‐regulation of KCC2 function during development has the inevitable consequence of opening a major pathway for NH4+ influx, which can be relevant under pathophysiological conditions.


Journal of Neuroscience Research | 2015

A reliable model for gamma oscillations in hippocampal tissue

Justus Schneider; Andrea Lewen; Thuy-Truc Ta; Lukas V. Galow; Raffaella Isola; Ismini E. Papageorgiou; Oliver Kann

Gamma oscillations (30–100 Hz) reflect a fast brain rhythm that provides a fundamental mechanism of complex neuronal information processing in the hippocampus and in the neocortex in vivo. Gamma oscillations have been implicated in higher brain functions, such as sensory perception, motor activity, and memory formation. Experimental studies on synaptic transmission and bioenergetics underlying gamma oscillations have primarily used acute slices of the hippocampus. This study tests whether organotypic hippocampal slice cultures of the rat provide an alternative model for cortical gamma oscillations in vitro. Our findings are that 1) slice cultures feature well‐preserved laminated architecture and neuronal morphology; 2) slice cultures of different maturation stages (7–28 days in vitro) reliably express gamma oscillations at about 40 Hz as induced by cholinergic (acetylcholine) or glutamatergic (kainate) receptor agonists; 3) the peak frequency of gamma oscillations depends on the temperature, with an increase of ∼3.5 Hz per degree Celsius for the range of 28–36°C; 4) most slice cultures show persistent gamma oscillations for ∼1 hr during electrophysiological local field potential recordings, and later alterations may occur; and 5) in slice cultures, glucose at a concentration of 5 mM in the recording solution is sufficient to power gamma oscillations, and additional energy substrate supply with monocarboxylate metabolite lactate (2 mM) exclusively increases the peak frequency by ∼4 Hz. This study shows that organotypic hippocampal slice cultures provide a reliable model to study agonist‐induced gamma oscillations at glucose levels near the physiological range.


Brain Structure & Function | 2015

Widespread activation of microglial cells in the hippocampus of chronic epileptic rats correlates only partially with neurodegeneration

Ismini E. Papageorgiou; Andriani F. Fetani; Andrea Lewen; Uwe Heinemann; Oliver Kann

Abstract Activation of microglial cells (brain macrophages) soon after status epilepticus has been suggested to be critical for the pathogenesis of mesial temporal lobe epilepsy (MTLE). However, microglial activation in the chronic phase of experimental MTLE has been scarcely addressed. In this study, we questioned whether microglial activation persists in the hippocampus of pilocarpine-treated, epileptic Wistar rats and to which extent it is associated with segmental neurodegeneration. Microglial cells were immunostained for the universal microglial marker, ionized calcium-binding adapter molecule-1 and the activation marker, CD11b (also known as OX42, Mac-1). Using quantitative morphology, i.e., stereology and Neurolucida-based reconstructions, we investigated morphological correlates of microglial activation such as cell number, ramification, somatic size and shape. We find that microglial cells in epileptic rats feature widespread, activation-related morphological changes such as increase in cell number density, massive up-regulation of CD11b and de-ramification. The parameters show heterogeneity in different hippocampal subregions. For instance, de-ramification is most prominent in the outer molecular layer of the dentate gyrus, whereas CD11b expression dominates in hilus. Interestingly, microglial activation only partially correlates with segmental neurodegeneration. Major neuronal death in the hilus, CA3 and CA1 coincides with strong up-regulation of CD11b. However, microglial activation is also observed in subregions that do not feature neurodegeneration, such as the molecular and granular layer of the dentate gyrus. This in vivo study provides solid experimental evidence that microglial cells feature widespread heterogeneous activation that only partially correlates with hippocampal segmental neuronal loss in experimental MTLE.


Pflügers Archiv: European Journal of Physiology | 1996

(-)-BACLOFEN-INDUCED AND CONSTITUTIVELY ACTIVE INWARDLY RECTIFYING POTASSIUM CONDUCTANCES IN CULTURED RAT MIDBRAIN NEURONS

J. F. X. O'callaghan; Wolfgang Jarolimek; Andrea Lewen; Ulrich Misgeld

Abstract Biophysical and pharmacological properties, and development of the (–)-baclofen-induced potassium (KBac) conductance and the constitutively active inwardly rectifying potassium (KIR) conductance were characterised using the patch-clamp technique in cultured embryonic rat midbrain neurons. KBac conductance was induced by (–)-baclofen acting on γ-aminobutyric acid B (GABAB) receptors, and displayed a high degree of selectivity for potassium ions, an approximate square-root dependence of conductance on extracellular potassium concentration and strongly voltage-dependent activation. Ba2+ blocked the conductance in a voltage-independent manner, whereas Cs+ produced a voltage-dependent block. In the same preparation, the KIR conductance displayed biophysical properties indistinguishable from those of the KBac conductance. Block of KIR currents by Ba2+ was voltage independent (KI, 4 μM), whereas Cs+ produced a voltage-dependent block (KI, 370 μM at –100 mV, equivalent valence, z′, 1.67). The KBac and KIR conductances additionally displayed a strikingly similar pattern of development in culture; the specific conductance (nS/pF) of both conductances increased two- to three-fold between the first and second week in vitro, and remained constant thereafter.


Neuroscience Letters | 1995

5,7-Dihydroxytryptamine uptake discriminates living serotonergic cells from dopaminergic cells in rat midbrain culture ☆

Jutta Rohrbacher; Kerstin Krieglstein; Stefanie Honerkamp; Andrea Lewen; Ulrich Misgeld

Dissociated cells from embryonic rat midbrain develop in dissociated culture into glutamatergic, GABAergic and aminergic cells. The autofluorescent serotonin analogue, 5,7-dihydroxytryptamine (5,7-DHT), is taken up by a small population of cells that is immunoreactive to 5-hydroxytryptamine. Tyrosine hydroxylase-immunoreactive cells do not accumulate 5,7-DHT. 5,7-DHT uptake, therefore, is well suited for the identification of living serotonergic cells and their discrimination from dopaminergic cells.


The Journal of Neuroscience | 1999

A Furosemide-Sensitive K+–Cl−Cotransporter Counteracts Intracellular Cl− Accumulation and Depletion in Cultured Rat Midbrain Neurons

Wolfgang Jarolimek; Andrea Lewen; Ulrich Misgeld

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