Postpartum manifestation of a necrotising lipid storage myopathy associated with muscle carnitine deficiency.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
H Köller
Publications and source records attributed to H Köller.
TNF alpha in cerebrospinal fluid of meningitis patients reduces astrocytes membrane potential.
During inflammatory CNS diseases cytokines are released into the cerebrospinal fluid (CSF). Astrocytes which are target cells for cytokines also contribute importantly to undisturbed neuronal function e.g. by maintaining local ion homeostasis. The effects of CSF from patients with septic (CSF-SM) and aseptic (CSF-ASM) meningitis on electrophysiological membrane properties of cultured rat cortical astrocytes were investigated. Astrocytes significantly depolarized from a membrane potential of -75.6 +/- 2.3 to -47.4 +/- 6.2 mV in CSF-SM (n = 8). 12 of 18 CSF-ASM also induced a depolarization. The depolarization of astrocytes was inhibited by a neutralizing anti-TNF alpha antibody, indicating that the cytokine TNF alpha initiates the depolarization.
Animals↗
Immunologically induced electrophysiological dysfunction: implications for inflammatory diseases of the CNS and PNS.
During inflammation of the central or peripheral nervous system, a high number of immunologically active molecules, including bacterial or viral products as well as host-derived cytokines, are released. Patients suffering from inflammatory CNS or PNS diseases often develop transient symptoms with a rapid recovery, which obviously cannot be accounted for by immunologically induced tissue damage. These observations led to the hypothesis that immunologically active molecules can affect directly the electrophysiological functions of neurons and glial cells. Evidence for this hypothesis came from in vitro studies showing that cytokines, such as interleukins or tumor necrosis factors, arachidonic acid and its metabolites, interfere with electrophysiological properties of neurons or glial cells. These molecules affect ion currents, intracellular Ca2+ homeostasis, membrane potentials, and suppress or enhance the induction and maintenance of long-term potentiation. Similarly, virus proteins from human immunodeficiency virus type I were found to alter intracellular Ca2+ concentrations of neurons and astrocytes by modulating either transmitter receptors and channels or membrane transporters. Cerebrospinal fluid from MS patients contains factors which increase Na+ current inactivation and thereby reduce neuronal excitability. Immunoglobulins in sera of patients suffering from multifocal motor neuropathy and from acquired neuromyotonia interfere with nerve fibers, inducing alterations of conduction. Increased knowledge of these mechanisms will help to explain the pathogenesis of neurological symptoms and may provide a rationale for new therapeutic strategies.
Bacterial Infections↗
Cerebrospinal fluid from multiple sclerosis patients inactivates neuronal Na+ current.
Multiple sclerosis is a common inflammatory disease of the CNS. A great number of immunologically active molecules have been identified in the CSF of these patients (CSF-MS), but the role of these substances in neuronal dysfunction, especially in the origin of transient symptoms, is unclear. Therefore, we investigated the effect of CSF from 13 multiple sclerosis patients on membrane currents of cultured cortical neurons from embryonic rat and compared it with the effect of CSF from 12 patients with non-inflammatory neurological diseases. We found an increase in Na+ current (INa) inactivation by a shift of the hoo curve to more hyperpolarizing potentials by 9.3 mV. This effect was reversible by washing and could be abolished by CSF-MS heat inactivation. The degree of the shift ranged from 4.3 mV to 17.6 mV and correlated with the IgG index, but not with the degree of pleocytosis, protein or albumin content. The maximal amplitude of INa was unchanged. We concluded that diffusible factors are released into the CSF which reduce neuronal excitability and thereby disturb the function of the neuronal network. These factors may well contribute to transient neurological symptoms seen in patients with "active' multiple sclerosis.
Adolescent↗
Tumour necrosis factor-alpha increases intracellular Ca2+ and induces a depolarization in cultured astroglial cells.
Tumour necrosis factor (TNF)-alpha, a strong immune mediator, is released within the brain during inflammatory diseases and contributes to immunological activation of glial cells. Here we report that, in astrocytes, TNF-alpha also affects the intracellular Ca2+ homeostasis and basic electrophysiological properties such as the membrane potential. Using the Ca2+ indicator dye fura-2 in a cell culture model, we found that TNF-alpha (10-1000 U ml-1), but not interleukin 1 or 6, induced a slow but more than two-fold increase of the intracellular Ca2+ concentration, which could be blocked by Co2+ (1.0 mM), verapamil (100 microM) or omission of external Ca2+. This intracellular Ca2+ increase was accompanied by a marked decrease of the membrane potential by 35 mV. CSF of patients with bacterial meningitis, known to contain large amounts of TNF-alpha, induced a similar depolarization of astrocytes, which was markedly reduced by a neutralizing anti-TNF-alpha antibody. We conclude that TNF-alpha induces an increase of intracellular Ca2+ and a depolarization in astrocytes with the consequence of disturbing voltage-dependent glial functions such as regulation of local ion concentrations and glutamate uptake. During inflammatory CNS diseases this immuno-electrical coupling may contribute to an impairment of neuronal function.
Animals↗
Fever as sole and delayed manifestation of azathioprine hypersensitivity.
Explore the source record for details and available documents.
Azathioprine↗
Impairment of electrophysiological function of astrocytes by cerebrospinal fluid from a patient with Waldenström's macroglobulinemia.
Patients with the Bing Neel type of Waldenström's macroglobulinemia often present with global neurological symptoms. In this case report, we investigated the effects of cerebrospinal fluid (CSF) of a such a patients (CSF-WM), who presented with seizures and psychomotor slowing, on the electrophysiological properties of cultured rat neurons and astrocytes. Membrane potential and Na+ and K+ currents of neurons were unaffected. Astrocytes, however, were significantly depolarized from -77.6 +/- 8.2 mV to -48.0 +/- 7.6 mV (38%) by CSF-WM. The depolarization was markedly reduced after CSF-WM heat inactivation or after pre-incubation of astrocytes with dexamethasone (1 microM). Astrocytes are electrophysiologically active cells, which control local ionic micro-environment. Therefore, we conclude that global neurological symptoms in the Bing Neel type of Waldenström's macroglobulinemia like generalized seizures can result from an impairment of glial cells electrophysiological functions.
Aged↗
Bacterial endotoxins impair electrophysiological properties of cultured astrocytes but not of cultured neurons.
The endotoxins of bacteria are lipopolysaccharides which are released in the central nervous system during bacterial meningitis. Endotoxin titers in cerebrospinal fluid correspond to the appearance of severe neurological symptoms like seizures and coma. The pathogenic mechanism, however, by which endotoxins disturb neuronal function, is unclear. The functional deficit may originate either from direct alteration of neuronal excitability or from indirect effects mediated by glial cells. Therefore, we investigated the effects of lipopolysaccharides on electrophysiological properties of cortical neurons and astrocytes in separate cell cultures. Membrane potential, resistance and membrane currents of neurons were unaffected. By contrast, astrocytes depolarized markedly in a dose dependent manner (concentration range 1.0-10.0 micrograms/ml). The depolarization was Na+ dependent and amiloride sensitive (250 microM), both indicating an activation of an electrogenic sodium dependent transport system like the Na+/Ca2+ exchanger as a source of the depolarization. These results suggest that endotoxin induced neurological deficits are not caused by direct effects on neurons, but may result from an impaired glial cell function.
Amiloride↗
Lipopolysaccharides and leukotriene B4 induce independently regulated electrophysiological and immunological responses in cultured astrocytes.
Astrocytes play an important role in immunological processes within the central nervous system. They are able to produce cytokines like interleukin 6 (IL-6) and depolarize substantially after stimulation by lipopolysaccharides (LPS) or leukotriene B4 (LTB4). Therefore, we investigated the coupling between these immunological and electrophysiological processes. Amiloride (250 microM), a blocker of various Na+ transport systems, inhibited LPS (5 micrograms/ml)-induced depolarization, whereas the LPS-induced release of IL-6 was unaffected, indicating different intracellular regulatory mechanisms. LTB4 (1.0 microM) induced a depolarization of a similar degree but mediated by a different ionic mechanism and failed to induce a detectable IL-6 release. Dexamethasone (1.0 microM) and cycloheximide (2.0 microM) specifically reduced LTB4-induced depolarization, while LPS-induced depolarization was unaffected, providing further evidence for different regulatory pathways. Neither the depolarization nor the immunological stimuli served as a proliferation signal. These data demonstrate that independent immunological and electrophysiological responses with specific intracellular regulation are evoked after stimulation with LPS or LTB4. With respect to functional disturbance of depolarized glial cells, e.g. in maintaining local ionic homeostasis, neuronal excitability may be affected indirectly and by this way account for the appearance of neurological symptoms during inflammatory CNS diseases.
Animals↗
Deficiency of both protein C and protein S in a family with ischemic strokes in young adults.
Protein C and protein S deficiencies increase the risk of venous thrombosis and pulmonary embolism, but their role in arterial thrombosis or embolism is controversial. We describe cerebral ischemia in two young women in a family with inherited deficiencies of both proteins C and S and provide evidence that a combined deficiency of proteins C and S may be a high risk factor for ischemic stroke in young adults.
Adult↗
Impaired neuronal function induced by the immune mediator leukotriene B4.
Inflammatory cerebral processes, mediated by immunologically active substances or invading of macrophages are frequently associated with neuronal dysfunction. This study describes the effects of leukotriene B4 on membrane potential, membrane resistance and potassium currents of cultured cortical neurons from the embryonic rat. Leukotriene B4 (1 microM) did not depolarize cortical neurons but induced a reversible reduction of voltage-dependent potassium outward currents (IK) in a subpopulation of these cells (35%). The results suggest that, in comparison to astrocytes, cortical neurons lack receptors for LTB4 or its intracellular activation pathway. Immune mediators, such as leukotrienes, may contribute to neuronal dysfunction during inflammatory diseases by affecting neuronal membrane currents.
Animals↗
Strychnine-sensitive glycine receptors in cultured primary neurons from rat neocortex.
After 1 day in vitro (DIV) glycine (1 mM) evoked chloride-dependent membrane currents in about 50% of primary cultured rat neocortical neurons and more than 98% of the cells were glycine-sensitive after 2 DIV lasting for at least up to 12 DIV which was similar to GABA chemosensitivity. Strychnine (IC50 40 nM) and picrotoxin (30 microM) but not bicuculline (50 microM) blocked the glycine-evoked currents. The results provide evidence for a very early expression of glycine receptors on cortical neurons leading to a powerful chloride channel-operating capacity during early development.
Animals↗
Depolarization of cultured astrocytes by leukotriene B4. Evidence for the induction of a K+ conductance inhibitor.
Since astrocytes have been shown to participate in intracerebral immunological processes we investigated the effect of the immune mediators, leukotrienes (LT) B4, LTC4 and LTD4 on membrane properties of cultured astrocytes from neonatal rat brain. When LTB4 was added to the bath solution the membrane potential slowly decreased from -96 mV to -38 mV. While LTB4 at a concentration of 500 nM was ineffective, depolarization occurred when concentrations of 750 nM and above were used. The depolarizing effect was specific for LTB4, since LTC4 and LTD4, other arachidonic acid derivates, failed to depolarize astrocytes at even higher concentrations (1 microM). When the K+ conductance blocker, Ba2+ (2 mM), was added to the bath solution, astrocytes depolarized to the same degree but no further depolarization was achieved when LTB4 was added. Bath application of Co2+ (1 mM), in order to reduce putative Ca2+ inward currents or reduced internal chloride concentration, did not alter the LTB4-induced depolarization, thus arguing against additional Ca(2+)- or Cl(-)-dependent depolarizing effects. The LTB4-induced depolarization could be markedly reduced, however, by preincubation of the cells with cycloheximide (2 microM), which blocks translation and thereby protein synthesis. Cycloheximide alone had no effect on the membrane potential. These data indicate that, in astrocytes, LTB4 stimulates the synthesis of a protein, which, in turn, inhibits K+ conductances. This effect could impair glial, as well as neuronal, functions during CNS diseases accompanied by immunological processes.
Animals↗
Spontaneous activity and recurrent inhibition in cultured hippocampal networks.
As a model for an integrated neuronal network based on the concept of modular units, we have investigated the occurrence of spontaneous activity and the formation of synaptic circuits in primary cultures of dissociated hippocampal neurons from the embryonic rat. Sodium-dependent action potentials (APs) could be elicited after 1 day in vitro (DIV), whereas spontaneous postsynaptic potentials (PSPs), "miniature" PSPs and APs appeared after 3-6 DIV. The number of cells with spontaneous APs and the rate of APs increased during development of the neuritic network. In addition to a stochastic spike interval distribution, pyramid-shaped neurons could be identified after 10-12 DIV, which fired preferentially at interspike intervals between 20-120 ms and 190-400 ms. This distinctive bimodal interspike interval pattern was sensitive to GABA-A antagonists. Simultaneous recordings of pairs of neurons demonstrated recurrent inhibitory, GABA-ergic synaptic circuits. In addition, a subpopulation of GABAergic neurons could be visualized by immunocytochemistry. These results are discussed in relation to the hypothesis that spontaneous firing of connected neurons is network-driven, based on synaptic "noise" and patterned by recurrent inhibition.
Action Potentials↗
Paroxysmal long-lasting depolarizations in cultured hippocampal neurons are generated by activation of NMDA and non-NMDA receptors.
In primary cultures of hippocampal neurons from the embryonic rat, spontaneous depolarizations lasting up to 6 sec and resembling paroxysmal depolarization shifts (PDSs) appeared after 11 days in vitro. These depolarizations are presumably generated by synaptic events, because: (1) both their appearance and duration are independent of membrane potential, (2) the amplitudes of the underlying currents depend monotonically on membrane potential, and (3) they are reversed at the reversal potential of the excitatory postsynaptic potentials (EPSPs). In addition, PDSs disappeared reversibly when sodium-dependent action potentials were blocked by tetrodotoxin (10 microM) and when synaptic transmission was reduced by elevated Mg2+ (5 mM). Further, the fact that these depolarizations can appear simultaneously in two neurons in paired recordings also points to a synaptic origin. Inhibition of glutaminergic synaptic transmission by kynurenic acid (50 microM) and the NMDA-antagonist D-2-amino-5-phosphonovaleric acid (APV; 50 microM) led to a marked shortening of the depolarizations. This blocking effect of kynurenic acid and APV and comparison with the currents elicited by locally applied glutamate or NMDA provide evidence for an activation of both types of glutamate receptors to induce PDSs. The role of alteration of glutaminergic synaptic transmission in the induction and maintenance of these depolarizations is discussed in the context of results from the literature on the appearance of PDSs in cultures grown under chronic blockade of glutamate receptors.
2-Amino-5-phosphonovalerate↗
An improved graphical method for pattern recognition from spike trains of spontaneously active neurons.
Spontaneous activity and rhythmical oscillations are common features of large neuronal networks in mammals. Detection of repetitive spike patterns or pacemaker activity during electrophysiological recording of spontaneous action potentials from single neurons can be difficult if a "noisy" background is present. This paper describes an improved method for an online spike train analysis based on joint interval histograms (JIH, Rodiek et al. 1962). By means of higher ordered JIH the discrimination of spike patterns with repetitive bursting activity or oscillations is possible even when randomly distributed action potentials appear. Examples of simulated spike trains and those recorded from cultured hippocampal neurons are presented.
Animals↗
Electrophysiological properties of rat septal region neurons during development in culture.
We report on the development of membrane properties of septal region neurons from embryonic rats in serum-free culture during 1-25 days in vitro (DIV). Na(+)-dependent action potentials could be evoked within 1 day after plating and 3 different types of outward current were observed by means of the patch-clamp technique: IK, IA and IC. In some neurons the neurotransmitter GABA evoked a chloride current after 2 DIV. In addition a cationic current elicited by glutamate appeared after 4 DIV. Within 8-12 DIV virtually all neurons were sensitive to both GABA and glutamate. Spontaneous action potentials and postsynaptic potentials occurred after 7-10 DIV but cultured septal neurons did not generate any pacemaker-like activity.
Action Potentials↗
GABA and glutamate receptor development of cultured neurons from rat hippocampus, septal region, and neocortex.
The early development of functionally active GABA and glutamate receptors on neurons from hippocampus, septal region, and neocortex of embryonic rats were studied using primary dissociated serum-free cell cultures. The responses to GABA and glutamate, applied to individual neurons by pressure ejection, were tested at different developmental stages, starting at 1 day in vitro (DIV) until 3 weeks. In all three types of neuronal cultures, the GABAA-receptor developed prior to the glutamate receptors, and after 9 DIV most of the neurons were sensitive to both GABA and glutamate. N-methyl-D-aspartate (NMDA) and non-NMDA receptor subtypes of the glutamate receptors could be distinguished in hippocampal cultures. The development of GABA and glutamate receptors on septal region neurons appeared to be delayed as compared to hippocampal neurons. In neocortical cultures the majority of neurons was sensitive to GABA just after plating, whereas the sensitivity to glutamate was retarded. The differences in GABA and glutamate receptor development among these three neuronal cultures provide evidence that the appearance of transmitter receptors on cultured neurons is predominantly determined by intrinsic mechanisms rather than by environmental conditions. The proportion of spontaneously active networks in these cultures increased with a time course very similar to the rise in glutamate-sensitive neurons suggesting that functional active glutamate receptors may be involved in the generation of spontaneous activity.
Animals↗