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Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2-0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO[sub.2] abolished seizures within 20 s. CO[sub.2] also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the I[sub.h] current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes., Author(s): Sebastian Schuchmann [1, 7]; Dietmar Schmitz [2, 7]; Claudio Rivera [1, 3]; Sampsa Vanhatalo [4]; Benedikt Salmen [2]; Ken Mackie [5]; Sampsa T Sipila [1]; Juha Voipio [1]; Kai [...]

Cannabis consumption results in impaired learning. The proper synchronization of neuronal activity in the mammalian hippocampus gives rise to network rhythms that are implicated in memory formation. Here, we have studied the impact of cannabinoids on hippocampal sharp waves and associated ripple oscillations using field- and whole-cell voltage-clamp recordings. We demonstrate that the activation of cannabinoid receptor 1 suppresses sharp wave-ripples (SWRs) in mice in vivo and in vitro. This suppression was paralleled by a selective reduction of SWR-associated inward but not outward charge transfer, demonstrating an impairment of excitation due to cannabinoid exposure. Adenosine, a presynaptic modulator of glutamate release, mimicked and occluded the observed consequences of cannabinoids on SWRs. We conclude that inhibition of glutamatergic feed-forward excitation can explain cannabinoid-mediated disruption of SWRs and may account for cannabinoid-induced impairment of hippocampus-dependent memory. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

CO has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO can be used to suppress seizures in epilepsy patients. The effect of CO on cortical epileptic activity accompanying behavioral seizures was studied in rats and nonhuman primates, and based on these data, preliminary tests were carried out in humans. In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor cortex stimulation. Five percent CO was applied for 5 min, 3 min before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor cortex. Seven patients with drug-resistant partial epilepsy were examined with video-EEG (electroencephalography) and received 5% CO in medical carbogen shortly after electrographic seizure onset. In rats, 5% CO strongly suppressed cortical afterdischarges, by approximately 75%, whereas responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pCO from 37 to 44-45 mm Hg (corresponding to inhalation of 5% CO or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by approximately 25%. In a pilot trial carried out in seven patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO was started after seizure generalization. Five percent CO has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO can be used for acute treatment to suppress seizures in epilepsy patients. [ABSTRACT FROM AUTHOR]

The family of neuronal Ca2+ sensor (NCS) proteins is known to influence a variety of physiological and pathological processes by affecting signalling of different receptors and ion channels. Recently, it has been shown that the NCS protein VILIP-1 influences the activity of the receptor guanylyl cyclase GC-B. In transfected cell lines, VILIP-1 performs a Ca2+-dependent membrane association, the reversible Ca2+-myristoyl switch of VILIP-1, which leads to an increase in natriuretic peptide-stimulated cGMP levels. In this study, we have investigated the effect of VILIP-1 on cGMP signalling in C6 cells and in primary hippocampal neurons, where VILIP-1 and GC-B are co-expressed in many but not all neurons and partially co-localize in the soma and in dendrites. Our data indicate that VILIP-1 modulates GC-B activity by influencing clathrin-dependent receptor recycling. These data support a general physiological role for VILIP-1 in membrane trafficking in the intact hippocampus, where the NCS protein may affect processes, such as neuronal differentiation and synaptic plasticity e.g. by influencing cGMP-signalling. [ABSTRACT FROM AUTHOR]

The production of nitric oxide (NO) during low-Mg2+-induced epileptiform activity in rat hippocampal–entorhinal cortex slices was investigated by real-time monitoring using 1,2-diaminoanthraquinone (DAQ). NO reacts with the aromatic amino groups of DAQ at neutral pH and in the presence of oxygen to form the fluorescence product 1H-anthra-[1,2d]-[1,2,3]triazole-6,11-dione (ATD). The DAQ-induced formation of ATD required NO and was insensitive to radical oxygen species. Removal of Mg2+ ions from the artificial cerebrospinal fluid (ACSF) induced a significant elevation in the ATD fluorescence signal. The application of l-arginine (2 mM), a substrate of nitric oxide synthase (NOS), caused a comparable increase in the ATD fluorescence signal. Furthermore, ATD signal increase induced either by low-Mg2+ ACSF or by l-arginine was sensitive to N-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor. The application of L-NAME (200 μM) caused a complete blockade of low-Mg2+-induced epileptiform activity. Under this condition, increasing NO concentration by addition of the NO donor S-nitroso-N-acetylpenicillamine (200 μM) reinduced the epileptiform activity. It has been concluded that onset and maintenance of low-Mg2+-induced spontaneous epileptiform activity are modulated by NO concentration. Further NO imaging studies may help to elucidate the role of NO in detail and may bring to light new means for epilepsy therapy. [Copyright &y& Elsevier]

Abstract: In neonates, asphyxia is usually followed by hyperoxic treatment. In order to study whether hyperoxic reoxygenation might cause additional impairment of neuronal function, we subjected organotypic hippocampal slice cultures of juvenile rats (7 DIV, P6–8) to 30 min anoxia followed by 60 min hyperoxic or normoxic reoxygenation (95% or 19% O2, respectively). Spontaneous and evoked field potentials as well as [Ca2+]o were recorded in the pyramidal layer of area CA1 or area CA3. In area CA1, 30 min of anoxia led to decline of evoked field potential amplitudes by on average 67% and to profound changes in field potential characteristics and Ca2+ homeostasis which were not related to outcome after reoxygenation. Hyperoxic reoxygenation resulted first in a fast recovery of the field potential amplitude to 82% of the control value and then, in 75% of slice cultures, in a large negative field potential shift accompanied by a prolonged decrease of [Ca2+]o and loss of excitability outlasting the experiment. Recovery of field potential amplitude under normoxic conditions stayed poor, with a first increase to 51% and a second decrease to 22%. In contrast, field potential amplitude in area CA3 recovered to 80% of the initial amplitude, irrespective of the reoxygenation mode. The selective loss of function during hyperoxic reoxygenation in area CA1 might be a first sign of neuronal injury that we observed 1 h after end of hyperoxic reoxygenation in a previous study. Whether the poor outcome after normoxic reoxygenation would favour long-term recovery remains to be determined. [Copyright &y& Elsevier]