1,721,023 research outputs found
Glia-derived neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy
No full textThe conversion of cholesterol intopregnenolone by the enzyme cholesterolside-chain cleavage cytochromeP450 (P450scc) is the rate-limitingstep in the steroid synthesis. Glialcells and neurons both expressP450scc and synthesize neurosteroidsthat act as positive modulators ofGABAergic transmission. Astrocytesbecome activated following statusepilepticus (SE), but it is presently unclearwhether this activation leads toenhanced neurosteroid synthesis. Westudied the time course of P450sccimmunoreactivity changes afterpilocarpine-induced SE and its relationshipwith epileptogenesis. Wefound that P450scc is upregulated inthe CA3 hippocampal region, afterSE. Induction of P450scc was mainlyobserved in astrocytes identified by aGFAP antibody, although hemeoxygenase-1-positive microglial cells,RIP-positive oligodendrocytes andNeuN-neurons were also stained forP450scc (Fig. 1). The extent ofP450scc induction was directly relatedwith the onset of spontaneouslyrecurrent seizures in adult (8-weekold)rats. In addition, in young (3-week-old) rats the induction ofP450scc and the latent period durationwere much larger than in adultrats. To further evaluate the role ofP450scc upregulation, we used the5-reductase inhibitor finasteride(100 mg/kg/day for approximately 3weeks) to suppress the synthesis ofGABA-modulating neurosteroidssuch as allopregnanolone. Interestingly,adult epileptic rats, comparedwith a group of vehicle-treated ratsthat experienced a similar SE, presentedwith significantly (p<0.01) anticipatedgeneralized seizures whentreated with finasteride. In young rats,we observed early generalized seizuresin approximately 50% of the animals.These findings suggest thatneurosteroids can modulate epileptogenesisin the pilocarpine modelof temporal lobe epilepsy
Glia-neuron interactions: neurosteroids.
No full textGlial cells have both beneficial and detrimentaleffects on recovery from brain damage and playa role in epileptogenesis. Herein, we summarizeevidence indicating that the ability of astrocytesto produce neurosteroids that reinforce c-aminobutyricacid receptor A (GABAA) functionsimpinge on epileptogenesis, as shown in temporallobe epilepsy models. For an expanded treatmentof this topic see Jasper’s Basic Mechanisms of theEpilepsies, Fourth Edition (Noebels JL, Avoli M, RogawskiMA, Olsen RW, Delgado-Escueta AV, eds)published by Oxford University Press (available onthe NCBI Bookshelf)
Absence Seizures: Thalamocortical Synchronization and Absence Epilepsy
No full textGeneralized spike-and-wave (SW) discharges are often associated with periods of impaired consciousness (i.e., withabsence seizures) and reflect thalamocortical oscillations similar to those involved in sleep spindles, but at a lowerfrequency. Both cortical and thalamic neuronal networks contribute to SWdischarge. Moreover, according to recentevidence obtained from rodent models, discrete cortical networks initiate these seizures by producing enhancedcorticothalamic output activity that initiates the following sequence: (i) corticothalamic activity makes thalamicreticular γ-aminobutyric acid (GABA)-ergic cells fire intense action potential bursts; (ii) these bursts cause extended inhibitory postsynaptic potentials (IPSPs) in thalamic relaycells, which results in (iii) a slowing of relay cell pacing frequency and (iv) a recruitment of a larger number of corticaland thalamic neurons – which leads to SW activity. The changes that cause the initiating cortical hyperexcitabilityinclude both intrinsic and synaptic mechanisms
Does interictal activity sustain seizures and epileptogenesis?
No full textInterictal spiking is seen in the EEG of epileptic patients betweenseizures. To date, the roles played by interictal events in seizureoccurrence and in epileptogenesis remain elusive. While interictalspikes may herald the onset of electrographic seizures, experimentaldata indicate that hippocampus-driven interictal events preventseizure precipitation. Even less clear than the role of interictalevents in seizure occurrence is whether and how interictal spikescontribute to epileptogenesis. Thus, while plastic changes withinlimbic neuronal networks may result from ongoing interictal activity,experimental evidence supports the view that epileptogenesisis accompanied by a decrease in hippocampus-driven interictalactivity
Epileptiform hyperexcitability in the rat neocortex: modulation by the H current blocker ZD7288
No full textObjectives: Neurons in the CNS respond to intracellular injection of hyperpolarizing current pulses by generating depolarizing sags contributed by a cation current termed Ih. Ih modulates neuron excitability and rhythmicity. However, whether the net effect of Ih on cortical networks results in facilitation or depression of epileptiform activity remains debatable. Here, we addressed this issue by studying the effects of the Ih blocker ZD7288 on the epileptiform discharges.Methods: We studied with field and intracellular recordings the effects of the Ih blocker ZD7288 on the epileptiform discharges (duration=2.54±0.33s, mean±SEM; interval of occurrence=34.2±3.3s, n=30) induced in rat neocortical slices by bath applying 4- aminopyridine+picrotoxin+CGP55845.Results: ZD7288 (10–100μM; n=18) abolished the depolarizing sags seen during injection of intracellular hyperpolarizing current pulses while increasing both resting membrane potential and apparent input resistance. These effects were fully established with 10μM ZD7288 and were accompanied by a dosedependent decrease in the occurrence of spontaneous epileptiform events and a reduction in their duration (this last effect becoming apparent with concentrations >20μM). ZD7288 (10–100μM; n=17) also caused a dose-dependent decrease of background postsynaptic potentials. Finally, 10, 50 or 100μM ZD7288 (n=6, 5 and 8, respectively) depressed the epileptiform activity during application of Cs+, which is known to reduce Ih.Conclusion: This evidence indicates that ZD7288 depresses neocortical epileptiform synchronization. However, most of this action may reflect the ability of ZD7288 to interfer with synaptic transmission
Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy
No full textAcid-sensing ion channels (ASICs) constitute a recently discovered family of excitatory cation channels, structurally related to the superfamily of degenerin/epithelial sodium channels. ASIC1b and ASIC3 are highly expressed in primary sensory neurons and are thought to play a role in pain transmission related to acidosis. ASIC1a, ASIC2a, and ASIC2b are also distributed in the central nervous system where their function remains unclear. We investigated here the regulation of their expression during status epilepticus (SE), a condition in which neuronal overexcitation leads to acidosis. In animals treated with pilocarpine (380 mg/kg) to induce SE, we observed a marked decrease of ASlC2b mRNA levels in all hippocampal areas and of ASIC1a mRNA levels in the CA1-2 fields. These changes were also observed after protective treatment from neuronal cell death with diazepam (10 mg/kg) and pentobarbital (30 mg/kg). These findings suggest a key role of channels containing ASIC1a and ASIC2b subunits in both normal and pathological activity of hippocampus
Entorhinal cortex-subiculum interactions in an experimental model of mesial temporal lobe epilepsy
No full textMesial temporal lobe epilepsy (MTLE) patients present with seizures
involving the limbic system and with a pattern of brain damage characterized
by neuronal loss in CA1/CA3 areas, dentate hilus, and entorhinal
cortex (EC), layer III (Houser CR. Adv Neurol 1999;79:743–61). Similar
findings are seen in laboratory animals following pilocarpine injection
(Turski WA, et al. Behav Brain Res 1983;9:315–35). This procedure induces
an initial convulsive response, which is followed within 2–3 weeks
by recurrent seizures. Limbic network hyperexcitability in MTLE and
in animal models results from seizure-induced brain damage leading to
(a) synaptic reorganization (Cavazos JE, et al. J Neurosci 1991;11:2795–
803; Houser CR. Adv Neurol 1999;79:743–61) and (b) changes inGABA
receptor–mediated inhibition (Buhl EH, et al. Science 1996;271:369–7;
Doherty J, Dingledine R. J Neurosci 2001;21:2048–57. However, it is
unclear how these changes lead to a chronic epileptic condition.
CA3-driven interictal activity induced in normal brain tissue by epileptogenic
stimuli inhibits the EC from generating ictal discharges (Barbarosie
M, Avoli M. J Neurosci 1997;17:9308–14), suggesting that CA3
damage causes a decrease of hippocampal output activity that would
release EC ictogenesis and establish a chronic epileptic condition. Accordingly,
slices obtained from pilocarpine-treated epileptic mice respond
to 4-aminopyridine (4AP) application by generating (a) CA3-
driven interictal activity that is less frequent than in nonepileptic control
(NEC) tissue, and (b) ictal discharges that do not disappear over
time and propagate to the CA1-subiculum via the temporoammonic path
(D’Antuono M, et al. J Neurophysiol 2002;87:634–9). From these findings,
we predicted that limbic seizures result from EC–subiculum interactions.
Using brain slices obtained from pilocarpine-treated, epileptic
rats, we found that decreased CA3 output function, along with reverberation
between EC and subiculum networks, lead to in vitro epileptogenesis.
First, intense activation of EC and subiculum was identified
with intrinsic optical signal (IOS) recordings in pilocarpine-treated, but
not in NEC slices. Second, using field potential recordings during 4AP
application, we established that CA3-driven interictal activity occurs
at lower frequency in pilocarpine-treated slices and that disconnection
of the EC from the subiculum attenuates 4AP-induced ictal discharges
in pilocarpine-treated, but not in NEC slices. Third, the distribution
of FosB/FosB-related proteins in epileptic tissue demonstrated distinct patterns overlapping those seen with IOS recordings, with the highest
intensity in layer III of the lateral EC.
In conclusion, our data show that hippocampal damage in epileptic
rats, and perhaps in MTLE patients, hampers the ability of CA3 output
activity to control ictogenesis in the EC. Such a process is reinforced by
interactions between subiculum and EC networks
Glia-neuron interactions: neurosteroids and epileptogenesis.
No full textGlia can influence the outcome of an epileptogenic insult by controlling the recovery of neuronalnetworks and functions. In particular, glia may facilitate the establishment of epilepsy by impairedremoval of glutamate from synapses or by releasing inflammatory cytokines and excitatoryneurotransmitters, such as interleukin-1β or, respectively, glutamate, aspartate and D-serine.Opposed to these pro-excitatory/pro-epileptogenic mediators, glia can also release molecules thatrestrain neuronal excitability such as neurosteroids, which are potent modulators of inhibitorycurrents dependent on γ-aminobutyric acid (GABA) type A receptors. In normal conditions,neurosteroids are mainly synthesized in neurons by conversion of cholesterol to pregnenolone, a stepcatalyzed by the cytochrome P450 cholesterol-side chain cleavage enzyme (P450scc). Following anepileptogenic insult, astrocytes transform into reactive cells and express high levels of P450scc, thusbecoming major players in neurosteroid synthesis. In this context, we found that the degree ofP450scc expression in astrocytes dictates the duration of the latent period. In line with this view,inhibition of neurosteroid synthesis anticipates the establishment of chronic epilepsy only when theP450scc induction is intense and long lasting. Thus, we hypothesize that reactive astrocytes maydampen neuronal excitability in the course of epileptogenesis through neurosteroid-mediatedmechanisms that likely enhance GABAergic neurotransmission
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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