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Hyperexcitability
Kinds of Hyperexcitability Selected Abstracts(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo [1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide Is a Potent and Efficacious KCNQ2 Opener which Inhibits Induced Hyperexcitability of Rat Hippocampal Neurons.CHEMINFORM, Issue 31 2004Yong-Jin Wu Abstract For Abstract see ChemInform Abstract in Full Text. [source] Foot temperature in diabetic polyneuropathy: innocent bystander or unrecognized accomplice?DIABETIC MEDICINE, Issue 3 2005S. B. Rutkove Abstract Aim To explore mechanisms by which temperature could influence the pathogenesis and symptoms of diabetic polyneuropathy. Methods We conducted a literature review attempting to identify mechanisms by which diabetic polyneuropathy could be affected by temperature. Results Cooling can theoretically hasten the progression of diabetic polyneuropathy through several different mechanisms. Specifically, cooling can enhance neuronal ischaemia, increase formation of reactive oxygen species, slow axonal transport, increase protein kinase C activity, and interfere with immune function. Short-term temperature fluctuations (both warming and cooling) can initiate and exacerbate neuropathic pain by causing neuronal hyperexcitability and functional deafferentation. Although normal fluctuations of distal extremity temperature may be sufficient for these effects, impaired thermoregulation may make the distal extremities more susceptible to temperature extremes. Eventually, a ,vicious cycle' may ensue, resulting in neuronal deterioration with further disruption of temperature regulation. Limited epidemiological data suggest a higher prevalence of diabetic polyneuropathy in populations living in colder locations, supporting our hypothesis. Conclusions Variations in foot temperature may play an important but as yet unrecognized role in the development and symptoms of diabetic polyneuropathy. Further basic and clinical research exploring this concept could help elucidate the natural history of diabetic polyneuropathy and lead to novel therapeutic strategies. [source] Monogenic migraine syndromes highlight novel drug targetsDRUG DEVELOPMENT RESEARCH, Issue 7 2007J. Jay Gargus Abstract In the post-genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering ,2 Na,K-ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co-expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy,meaning meta-stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway,genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432,440, 2007. © 2008 Wiley-Liss, Inc. [source] Neuropathic pain: symptoms, models, and mechanismsDRUG DEVELOPMENT RESEARCH, Issue 4 2006Simon Beggs Abstract Peripheral neuropathic pain is the most debilitating of all clinical pain syndromes and affects a large and growing number of people worldwide. There are diverse causes for peripheral neuropathic pain, which may be experienced after traumatic nerve injury or from diseases that affect peripheral nerves, such as diabetes, HIV/AIDS, and cancer, and it can also result from toxic chemicals, such as cancer chemotherapy agents. Despite these varying causes, it is clear that neuropathic pain is due to persistent pathological alterations resulting in hyperexcitability in the peripheral and central nervous systems, and it is the neuropathology that must be targeted for effective therapy of which there is none presently available. Mechanistically, neuropathic pain is distinct from acute pain and inflammatory pain, for which many effective therapies are known. In this review, we describe the relationships between clinical symptoms and experimental models of peripheral neuropathic pain, and we provide a framework for understanding the potential mechanisms that involve primary neuronal dysfunction as well as pathological changes in neuron-glial signaling. Drug Dev. Res. 67:289,301, 2006. © 2006 Wiley-Liss, Inc. [source] Pursuing paradoxical proconvulsant prophylaxis for epileptogenesisEPILEPSIA, Issue 7 2009Caren Armstrong Summary There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid-targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long-term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long-term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants,even to proconvulsants,to find the ideal preventative strategy for acquired epilepsy. [source] Cellular mechanisms of cobalt-induced hippocampal epileptiform dischargesEPILEPSIA, Issue 1 2009Jiwei He Summary Purpose:, To explore the cellular mechanisms of cobalt-induced epileptiform discharges in mouse hippocampal slices. Methods:, Hippocampal slices were prepared from adult mice and briefly exposed to a CoCl2 -containing external solution. Population and single cell activities were examined via extracellular and whole-cell patch recordings. Results:, Brief cobalt exposure induced spontaneous, ictal-like discharges originating from the CA3 area. These discharges were suppressed by anticonvulsants, gap junction blockers, or by raising extracellular Ca2+, but their generation was not associated with overall hyperexcitability or impairment in GABAergic inhibition in the CA3 circuit. Electroencephalographic ictal discharges of similar waveforms were observed in behaving rats following intrahippocampal cobalt infusion. Discussion:, Mechanisms involving activity-dependent facilitation of gap junctional communication may play a major role in cobalt-induced epileptiform discharges. [source] Predictors of pharmacoresistant epilepsy: Pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsyEPILEPSIA, Issue 10 2008Alexandra M. Gastens Summary Purpose:, Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. Methods:, For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. Results:, Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated-plus maze test), behavioral hyperexcitability (approach-response, touch-response, pick-up tests), and learning and memory (Morris water maze). Discussion:, Our hypothesis that AED-resistant rats will show more severe behavioral and cognitive changes than AED-responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy. [source] A Magnetoencephalographic Study of Patients with Panayiotopoulos SyndromeEPILEPSIA, Issue 7 2005Osamu Kanazawa Summary:,Purpose: Panayiotopoulos syndrome (PS) is a newly identified type of benign childhood epilepsy characterized by ictal vomiting and eye deviation. It is usually accompanied by occipital spike discharges; however, its classification as an early-onset benign childhood occipital epilepsy is controversial. To characterize this condition further, we examined the localization of equivalent current dipoles (ECDs) of spike discharges by magnetoencephalography (MEG) in patients with PS. Methods: We studied 13 patients with a mean age at time of examination of 5 years (range, 3,14 years). MEG was measured by using a whole-head 204-channel neuromagnetometer with simultaneous EEG recordings. The estimated locations of ECDs of each peak of the spike discharges were overlaid on magnetic resonance images of the brain. Results: Eleven (84.6%) patients showed clustered ECDs in the areas alongside the parietooccipital sulcus (eight of 13; 61.5%) and/or the calcarine sulcus (four of 13; 30.8%). Despite Fp-O synchronization of the spike discharges in the scalp EEG of five patients, no frontal locations of ECDs were found. All five (38.5%) boys with sylvian seizures, who also showed clustered ECDs in rolandic areas, had an earlier age at onset and higher seizure frequency than did other patients. ECD orientations were regular in all but one patient, who showed irregular and dispersed ECDs alongside bilateral calcarine sulci. Conclusions: Our results demonstrate localized cortical hyperexcitability in the areas alongside major cortical sulci in PS and indicate that PS is closely related to benign childhood epilepsy with centrotemporal spikes. [source] Impaired M-Current and Neuronal ExcitabilityEPILEPSIA, Issue 2002Motohiro Okada Summary: ,Purpose: Benign familial neonatal convulsions (BFNC), a hereditary epilepsy, occurs specifically in newborns and remits spontaneously after this period. Several mutations of either KCNQ2 or KCNQ3, members of the KCNQ-related K+ -channel (KCNQ-channel) family, were identified as a cause of BFNC. Such mutations impair KCNQ-related M- current, an element of the inhibitory system in the central nervous system (CNS), and therefore are thought to result in neuronal hyperexcitability. Methods: To clarify the pathogenesis of BFNC, this study investigated the effects of the KCNQ channel on propagation of neuronal excitability using a 64-channel multielectrode dish (MED64) system for novel two-dimensional monitoring of evoked field potentials including fiber volley (FV) and field excitatory postsynaptic potential (fEPSP). Results: Dup996, a selective KCNQ-channel inhibitor, did not affect the amplitude of FV or fEPSP, but enhanced the FV and fEPSP propagation. The ,-aminobutyric acid (GABA)A -receptor antagonist, bicuculline, enhanced their propagation, whereas ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/glutamate-receptor antagonist, DNQX, reduced both amplitude and propagation of fEPSP without affecting those of FV. Under the condition of GABAA -receptor blockade by bicuculline, Dup996 enhanced the amplitude of fEPSP and propagation of FV and fEPSP without affecting the amplitude of FV. Dup996 enhanced the stimulating effects of bicuculline on the propagation and amplitude of FV and fEPSP, but it did not affect the inhibiting effects of DNQX. Conclusions: These results suggest that the occurrence of BFNC cannot be produced by KCNQ-channel dysfunction alone but by reciprocal action between impaired KCNQ channel and the other unknown. [source] Characterization of Neuronal Migration Disorders in Neocortical Structures: Loss or Preservation of Inhibitory Interneurons?EPILEPSIA, Issue 7 2000Petra Schwarz Summary: Purpose: Neuronal migration disorders (NMD) are often associated with therapy-resistant epilepsy. In human cerebral cortex, this hyperexcitability has been correlated with a loss of inhibitory interneurons. We used a rat model of focal cortical NMD (microgyria) to determine whether the expression of epileptiform activity in this model coincides with a decrease in inhibitory interneurons. Methods: In 2- to 4-month-old rats, the density of interneurons immunoreactive for ,-aminobutyric acid (GABA), cal-bindin, and parvalbumin was determined in fronto-parietal cortex in nine 200-,m-wide sectors located up to 2.5 mm lateral and 2.0 mm medial from the lesion center in primary parietal cortex (Par 1). Quantitative measurements in homotopic areas of age-matched sham-operated rats served as controls. Results: The freeze lesion performed in newborn rat cortex resulted in adult rats with a microgyrus extending in a rostro-caudal direction from frontal to occipital cortex. The density of GABA- and parvalbumin-positive neurons in fronto-parietal cortex was not significantly different between lesioned and control animals. Only the density of calbindin-immunoreactive neurons located 1.0 mm lateral and 0.5 mm medial from the lesion was significantly (Student t test, p > 0.05) larger in freeze-lesioned rats (5.817 ± 562 and 6,400 ± 795 cells per mm3, respectively; n = 12) compared with measurements in homotopic regions in Parl cortex of controls (4,507 ± 281 and 4,061 ± 319 cells per mm3, respectively; n = 5). Conclusions: The previously reported widespread functional changes in this model of cortical NMD are not related to a general loss of inhibitory interneurons. Other factors, such as a decrease in GABA receptor density, modifications in GABAA receptor subunit composition, or alterations in the excitatory network, e.g., an increase in the density of calbindin-immunoreactive pyramidal cells, more likely contribute to the global disinhibition and widespread expression of pathophysiological activity in this model of cortical NMD. [source] CLINICAL STUDY: Abnormalities in cortical and transcallosal inhibitory mechanisms in subjects at high risk for alcohol dependence: a TMS studyADDICTION BIOLOGY, Issue 3-4 2008Kesavan Muralidharan ABSTRACT Central nervous system (CNS) hyperexcitability and a resulting state of behavioral undercontrol are thought to underlie the vulnerability to early-onset alcohol dependence (AD). The aim of this study was to explore the differences in the functioning of cortical inhibitory systems, utilizing transcranial magnetic stimulation (TMS), in subjects at high risk (HR) and low risk (LR) for AD and to examine the relationship between CNS inhibition and behavioral undercontrol. Right-handed HR (n = 15) and LR (n = 15) subjects, matched for age, gender, height, weight and education, were assessed for psychopathology and family history of alcoholism using the Semi-Structured Assessment for the Genetics of Alcoholism and the Family Interview for Genetic Studies. Following single-pulse TMS, an electromyogram recorded from the right opponens pollicis muscle was used to measure the silent periods at different stimulus intensities. HR subjects had significantly shorter contralateral and ipsilateral (iSP) silent periods and a relatively higher prevalence of ,absent' iSP. They had significantly higher mean externalizing symptoms scores (ESS) than LR subjects, and there was a significant negative correlation between iSP duration and ESS. These preliminary findings suggest that HR subjects have relative impairments in corticocortical and transcallosal inhibitory mechanisms. The consequent state of CNS hyperexcitability may be etiologically linked to the excess of externalizing behaviors observed in this population, which is thought to be a predisposition to a higher risk of developing early-onset alcoholism. [source] N -methyl- d -aspartate, hyperpolarization-activated cation current (Ih) and ,-aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2010Mohamed Ouardouz Abstract Febrile seizures are the most common types of seizure in children, and are generally considered to be benign. However, febrile seizures in children with dysgenesis have been associated with the development of temporal lobe epilepsy. We have previously shown in a rat model of dysgenesis (cortical freeze lesion) and hyperthermia-induced seizures that 86% of these animals developed recurrent seizures in adulthood. The cellular changes underlying the increased risk of epileptogenesis in this model are not known. Using whole cell patch-clamp recordings from CA1 hippocampal pyramidal cells, we found a more pronounced increase in excitability in rats with both hyperthermic seizures and dysgenesis than in rats with hyperthermic seizures alone or dysgenesis alone. The change was found to be secondary to an increase in N -methyl- d -aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs). Inversely, hyperpolarization-activated cation current was more pronounced in naïve rats with hyperthermic seizures than in rats with dysgenesis and hyperthermic seizures or with dysgenesis alone. The increase in GABAA -mediated inhibition observed was comparable in rats with or without dysgenesis after hyperthermic seizures, whereas no changes were observed in rats with dysgenesis alone. Our work indicates that in this two-hit model, changes in NMDA receptor-mediated EPSCs may facilitate epileptogenesis following febrile seizures. Changes in the hyperpolarization-activated cation currents may represent a protective reaction and act by damping the NMDA receptor-mediated hyperexcitability, rather than converting inhibition into excitation. These findings provide a new hypothesis of cellular changes following hyperthermic seizures in predisposed individuals, and may help in the design of therapeutic strategies to prevent epileptogenesis following prolonged febrile seizures. [source] Molecular analysis of the A322D mutation in the GABAA receptor ,1 -subunit causing juvenile myoclonic epilepsyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005Klaus Krampfl Abstract Juvenile myoclonic epilepsy (JME) belongs to the most common forms of hereditary epilepsy, the idiopathic generalized epilepsies. Although the mode of inheritance is usually complex, mutations in single genes have been shown to cause the disease in some families with autosomal dominant inheritance. The first mutation in a multigeneration JME family has been recently found in the ,1 -subunit of the GABAA receptor (GABRA1), predicting the single amino acid substitution A322D. We further characterized the functional consequences of this mutation by coexpressing ,1 -, ,2 - and ,2 -subunits in human embryonic kidney (HEK293) cells. By using an ultrafast application system, mutant receptors have shown reduced macroscopic current amplitudes at saturating GABA concentrations and a highly reduced affinity to GABA compared to the wild-type (WT). Dose,response curves for current amplitudes, activation kinetics, and GABA-dependent desensitization parameters showed a parallel shift towards 30- to 40-fold higher GABA concentrations. Both deactivation and resensitization kinetics were considerably accelerated in mutant channels. In addition, mutant receptors labelled with enhanced green fluorescent protein (EGFP) were not integrated in the cell membrane, in contrast to WT receptors. Therefore, the A322D mutation leads to a severe loss-of-function of the human GABAA receptor by several mechanisms, including reduced surface expression, reduced GABA-sensitivity, and accelerated deactivation. These molecular defects could decrease and shorten the resulting inhibitory postsynaptic currents (IPSCs) in vivo, which can induce a hyperexcitability of the postsynaptic membrane and explain the occurrence of epileptic seizures. [source] Distribution and regulation of L-type calcium channels in deep dorsal horn neurons after sciatic nerve injury in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2005E. Dobremez Abstract Deep dorsal horn neurons are involved in the processing of nociceptive information in the spinal cord. Previous studies revealed a role of the intrinsic bioelectrical properties (plateau potentials) of deep dorsal horn neuron in neuronal hyperexcitability, indicating their function in pain sensitization. These properties were considered to rely on L -type calcium currents. Two different isotypes of L -type calcium channel alpha 1 subunit have been cloned (CaV1.2 and CaV1.3). Both are known to be expressed in the spinal cord. However, no data were available on their subcellular localization. Moreover, possible changes in CaV1.2 and CaV1.3 expression had never been investigated in nerve injury models. Our study provides evidence for a differential expression of CaV1.2 and CaV1.3 subunits in the somato-dendritic compartment of deep dorsal horn neurons. CaV1.2 immunoreactivity is restricted to the soma and proximal dendrites whereas CaV1.3 immunoreactivity is found in the whole somato-dendritic compartment, up to distal dendritic segments. Moreover, these specific immunoreactive patterns are also found in electrophysiologically identified deep dorsal horn neurons expressing plateau potentials. After nerve injury, namely total axotomy or partial nerve ligation, CaV1.2 and CaV1.3 expression undergo differential changes, showing up- and down-regulation, respectively, both at the protein and at the mRNA levels. Taken together, our data support the role of L-type calcium channels in the control of intrinsic biolectrical regenerative properties. Furthermore, CaV1.2 and CaV1.3 subunits may have distinct and specific roles in sensory processing in the dorsal horn of the spinal cord, the former being most likely involved in long-term changes after nerve injury. [source] Enhancement of steady-state auditory evoked magnetic fields in tinnitusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2004Eugen Diesch Abstract The steady-state auditory evoked magnetic field and the Pbm, the magnetic counterpart of the second frontocentrally positive middle latency component of the transitory auditory evoked potential, were measured in ten tinnitus patients using a 122-channel gradiometer system. The patients had varying degrees of hearing loss. In all patients, the tinnitus frequency was located above the frequency of the audiometric edge, i.e. the location on the frequency axis above which hearing loss increases more rapidly. Stimuli were amplitude-modulated sinusoids with carrier frequencies at the tinnitus frequency, the audiometric edge, two frequencies below the audiometric edge, and two frequencies between the audiometric edge and the tinnitus frequency. Below the audiometric edge, the root-mean-square field amplitude of the steady-state response computed across the whole head as well as the contralateral and the ipsilateral dipole moment decreased as a function of carrier frequency. With carrier frequency above the audiometric edge, the steady-state response increased again. The amplitudes of the transitory Pbm component were patterned in a qualitatively similar way, but without the differences being significant. For the steady-state response, both whole-head root-mean-square field amplitude and the dipole moment of the sources at the tinnitus frequency showed significant positive correlations with subjective ratings of tinnitus intensity and intrusiveness. These correlations remained significant when the influence of hearing loss was partialled out. The observed steady-state response amplitude pattern likely reflects an enhanced state of excitability of the frequency region in primary auditory cortex above the audiometric edge. The relationship of tinnitus to auditory cortex hyperexcitability and its independence of hearing loss is discussed with reference to loss of surround inhibition in and map reorganization of primary auditory cortex. [source] Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTP,S binding in the dorsal horn of the spinal cord of noninflamed and inflamed ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2000L. J. Drew Abstract The analgesic potential of cannabinoid (CB) receptor agonists is of clinical interest. Improved understanding of the mechanisms of action of cannabinoids at sites involved in the modulation of acute and sustained inflammatory nociceptive transmission, such as the spinal cord, is essential. In vivo electrophysiology was used to compare the effect of the synthetic CB agonist, HU210, on acute transcutaneous electrical-evoked responses of dorsal horn neurons of noninflamed anaesthetized rats and anaesthetized rats with a peripheral carrageenin inflammation. CB receptor G-protein coupling in lumbar spinal cord sections of noninflamed and carrageenin-inflamed rats was studied with in vitro autoradiography of guanylyl 5,-[,-[35S]thio]triphosphate ([35S]GTP,S) binding. Spinal HU210 significantly inhibited the C-fibre-mediated late (300,800 ms) postdischarge response of dorsal horn neurons of noninflamed and carrageenin-inflamed rats; the CB1 receptor antagonist SR141716A blocked the effect of HU210. HU210 had limited effects on A-fibre-evoked dorsal horn neuronal responses of both groups of rats. HU210 significantly increased [35S]GTP,S binding in the dorsal horn of the spinal cord of both groups of rats compared with basal [35S]GTP,S binding; SR141716A blocked these effects. The predominant effect of spinal HU210, via CB1 receptor activation, was on the C-fibre driven postdischarge responses, a measure of neuronal hyperexcitability following repetitive C-fibre stimulation. Sustained, but not enhanced, antinociceptive effects of HU210 following carrageenin inflammation are reported; CB receptor G-protein coupling was not altered by inflammation. These results strengthen the body of evidence suggesting CB agonists may be an important novel analgesic approach for the treatment of sustained pain states. [source] A polygenic heterogeneity model for common epilepsies with complex geneticsGENES, BRAIN AND BEHAVIOR, Issue 7 2007L. M. Dibbens Approximately 40% of epilepsy has a complex genetic basis with an unknown number of susceptibility genes. The effect of each susceptibility gene acting alone is insufficient to account for seizure phenotypes, but certain numbers or combinations of variations in susceptibility genes are predicted to raise the level of neuronal hyperexcitability above a seizure threshold for a given individual in a given environment. Identities of susceptibility genes are beginning to be determined, initially by translation of knowledge gained from gene discovery in the monogenic epilepsies. This entrée into idiopathic epilepsies with complex genetics has led to the experimental validation of susceptibility variants in the first few susceptibility genes. The genetic architecture so far emerging from these results is consistent with what we have designated as a polygenic heterogeneity model for the epilepsies with complex genetics. [source] Altered functional properties of satellite glial cells in compressed spinal gangliaGLIA, Issue 15 2009Haijun Zhang Abstract The cell bodies of sensory neurons in the dorsal root ganglion (DRG) are enveloped by satellite glial cells (SGCs). In an animal model of intervertebral foraminal stenosis and low-back pain, a chronic compression of the DRG (CCD) increases the excitability of neuronal cell bodies in the compressed ganglion. The morphological and electrophysiological properties of SGCs were investigated in both CCD and uninjured, control lumbar DRGs. SGCs responded within 12 h of the onset of CCD as indicated by an increased expression of glial fibrillary acidic protein (GFAP) in the compressed DRG but to lesser extent in neighboring or contralateral DRGs. Within 1 week, coupling through gap junctions between SGCs was significantly enhanced in the compressed ganglion. Under whole-cell patch clamp recordings, inward and outward potassium currents, but not sodium currents, were detected in individual SGCs. SGCs enveloping differently sized neurons had similar electrophysiological properties. SGCs in the compressed vs. control DRG exhibited significantly reduced inwardly rectifying potassium currents (Kir), increased input resistances and positively shifted resting membrane potentials. The reduction in Kir was greater for nociceptive medium-sized neurons compared to non-nociceptive neurons. Kir currents of SGCs around spontaneously active neurons were significantly reduced 1 day after compression but recovered by 7 days. These data demonstrate rapid alterations in glial membrane currents and GFAP expression in close temporal association with the development of neuronal hyperexcitability in the CCD model of neuropathic pain. However, these alterations are not fully sustained and suggest other mechanisms for the maintenance of the hyperexcitable state. © 2009 Wiley-Liss, Inc. [source] Functional changes in astroglial cells in epilepsyGLIA, Issue 5 2006Devin K. Binder Abstract Epilepsy comprises a group of disorders characterized by the periodic occurrence of seizures, and pathologic specimens from patients with temporal lobe epilepsy demonstrate marked reactive gliosis. Since recent studies have implicated glial cells in novel physiological roles in the CNS, such as modulation of synaptic transmission, it is plausible that glial cells may have a functional role in the hyperexcitability characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors and transporters have all been associated with the epileptic state. This review integrates the current evidence regarding astroglial dysfunction in epilepsy and the potential underlying mechanisms of hyperexcitability. Functional understanding of the cellular and molecular alterations of astroglia-dependent hyperexcitability will help to clarify the physiological role of astrocytes in neural function as well as lead to the identification of novel therapeutic targets. © 2006 Wiley-Liss, Inc. [source] Contrasts in cortical magnesium, phospholipid and energy metabolism between migraine syndromes.HEADACHE, Issue 4 2003MD Boska Neurology. 2002;58:1227-1233. BACKGROUND: Previous single voxel (31)P MRS pilot studies of migraine patients have suggested that disordered energy metabolism or Mg(2+) deficiencies may be responsible for hyperexcitability of neuronal tissue in migraine patients. These studies were extended to include multiple brain regions and larger numbers of patients by multislice (31)P MR spectroscopic imaging. METHODS: Migraine with aura (MWA), migraine without aura (MwoA), and hemiplegic migraine patients were studied between attacks by (31)P MRS imaging using a 3-T scanner. RESULTS: Results were compared with those in healthy control subjects without headache. In MwoA, consistent increases in phosphodiester concentration [PDE] were measured in most brain regions, with a trend toward increase in [Mg(2+)] in posterior brain. In MWA, phosphocreatine concentration ([PCr]) was decreased to a minor degree in anterior brain regions and a trend toward decreased [Mg(2+)] was observed in posterior slice 1, but no consistent changes were found in phosphomonoester concentration [PME], [PDE], inorganic phosphate concentration ([Pi]), or pH. In hemiplegic migraine patients, [PCr] had a tendency to be lower, and [Mg(2+)] was significantly lower than in the posterior brain regions of control subjects. Trend analysis showed a significant decrease of brain [Mg(2+)] and [PDE] in posterior brain regions with increasing severity of neurologic symptoms. CONCLUSIONS: Overall, the results support no substantial or consistent abnormalities of energy metabolism, but it is hypothesized that disturbances in magnesium ion homeostasis may contribute to brain cortex hyperexcitability and the pathogenesis of migraine syndromes associated with neurologic symptoms. In contrast, migraine patients without a neurologic aura may exhibit compensatory changes in [Mg(2+)] and membrane phospholipids that counteract cortical excitability. Comment: If the theory of hyperexcitability of migraine brain is correct, basic scientists will need to find clear markers for the neuronal abnormalities that underlie this excitability. Using their techniques, these researchers could not find such markers. SJT [source] Interictal and Postictal Contingent Negative Variation in Migraine Without AuraHEADACHE, Issue 1 2001E.J.C.M. Mulder MSc Cortical hyperexcitability is thought to explain the more enhanced contingent negative variation (CNV) amplitudes and impaired CNV habituation that have been found during the interictal period in migraine without aura. These CNV characteristics have been shown to normalize to the level of healthy controls during an attack. This study aimed to replicate the interictal findings, and additionally examine whether migraineurs show reduced CNV amplitudes during the postattack period. Of 12 patients with migraine without aura and their sex- and age-matched healthy controls, CNV characteristics were recorded once in an interictal period, once during the postattack period within 30 hours after an attack that was treated with sumatriptan, and once after an attack that was treated with habitual nonvasoactive medication (counterbalanced). The present results did not confirm the enhanced CNV early and late wave amplitudes or impaired habituation, and cortical hyperexcitability that have previously been reported in the interictal period in patients with migraine without aura. During the postattack period, a decrease in CNV early and late amplitudes was found but only after sumatriptan use. This reduction in CNV amplitudes was most prominent over the frontal cortex and could reflect cortical hypoexcitability, possibly related to a suppression of central catecholaminergic activity by sumatriptan. [source] Sensory function and pain in a population of patients treated for breast cancerACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2009O. J. VILHOLM Background: Chronic pain is often reported after surgery for breast cancer. This study examined pain and sensory abnormalities in women following breast cancer surgery. Methods: Sensory tests were carried out on the operated and contra-lateral side in 55 women with chronic pain after breast cancer treatment and in a reference group of 27 pain-free women, who had also undergone treatment for breast cancer. Testing included a numeric rating score of spontaneous pain, detection and pain threshold to thermal and dynamic mechanical stimuli and temporal summation to repetitive pinprick stimulation. The neuropathic pain symptom inventory was applied for participants with chronic pain. Results: The mean age was 58.6 years for the pain patients and 60.6 years for the pain-free patients. Thermal thresholds were significantly higher on the operated side than on the contra-lateral side in both groups and side difference in warmth detection threshold was significantly higher in the pain group than in the pain-free group (mean 3.8 °C vs. 1.1 °C, P=0.01). The frequency of cold allodynia was higher in participants with pain than in pain-free participants (15/53 vs. 1/25, P=0.01), and the frequency of temporal summation evoked by repetitive pinprick was higher in participants with pain than in pain-free participants (23/53 vs. 2/25, P=0.0009). The frequency of dynamic mechanical allodynia did not differ significantly between the two groups. Conclusion: These findings suggest that chronic pain after surgery for breast cancer is associated with sensory hyperexcitability and is a neuropathic pain condition. [source] Gene Expression in the Neuropeptide Y System During Ethanol Withdrawal Kindling in RatsALCOHOLISM, Issue 3 2010Janne D. Olling Background:, Multiple episodes of ethanol intoxication and withdrawal result in progressive, irreversible intensification of the withdrawal reaction, a process termed "ethanol withdrawal kindling." Previous studies show that a single episode of chronic ethanol intoxication and withdrawal causes prominent changes in neuropeptide Y (NPY) and its receptors that have been implicated in regulating withdrawal hyperexcitability. This study for the first time examined the NPY system during ethanol withdrawal kindling. Methods:, Ethanol withdrawal kindling was studied in rats receiving 16 episodes of 2 days of chronic ethanol intoxication by intragastric intubations followed by 5 days withdrawal. The study included 6 groups: 4 multiple withdrawal episode (MW) groups [peak withdrawal plus (MW+)/minus (MW,) seizures, 3-day (MW3d), and 1-month (MW1mth) withdrawal], a single withdrawal episode group (SW), and an isocalorically fed control group. Gene expression of NPY and its receptors Y1, Y2, and Y5 was studied in the hippocampal dentate gyrus (DG) and CA3/CA1, as well as piriform cortex (PirCx), and neocortex (NeoCx). Results:, MW+/, as well as SW groups showed decreased NPY gene expression in all hippocampal areas compared with controls, but, in the DG and CA3, decreases were significantly smaller in the MW, group compared with the SW group. In the MW+/, and SW groups, Y1, Y2, and Y5 mRNA levels were decreased in most brain areas compared with controls; however, decreases in Y1 and Y5 mRNA were augmented in the MW+/, groups compared with the SW group. The MW+ group differed from the MW, group in the PirCx, where Y2 gene expression was significantly higher. Conclusion:, Multiple withdrawal episodes reversibly decreased NPY and NPY receptor mRNA levels at peak withdrawal, with smaller decreases in NPY mRNA levels and augmented decreases in Y1/Y5 mRNA levels compared with a SW episode. Multiple withdrawal-induced seizures increased the Y2 mRNA levels in PirCx. These complex changes in NPY system gene expression could play a role in the ethanol withdrawal kindling process. [source] Sizing up Ethanol-Induced Plasticity: The Role of Small and Large Conductance Calcium-Activated Potassium ChannelsALCOHOLISM, Issue 7 2009Patrick J. Mulholland Small (SK) and large conductance (BK) Ca2+ -activated K+ channels contribute to action potential repolarization, shape dendritic Ca2+spikes and postsynaptic responses, modulate the release of hormones and neurotransmitters, and contribute to hippocampal-dependent synaptic plasticity. Over the last decade, SK and BK channels have emerged as important targets for the development of acute ethanol tolerance and for altering neuronal excitability following chronic ethanol consumption. In this mini-review, we discuss new evidence implicating SK and BK channels in ethanol tolerance and ethanol-associated homeostatic plasticity. Findings from recent reports demonstrate that chronic ethanol produces a reduction in the function of SK channels in VTA dopaminergic and CA1 pyramidal neurons. It is hypothesized that the reduction in SK channel function increases the propensity for burst firing in VTA neurons and increases the likelihood for aberrant hyperexcitability during ethanol withdrawal in hippocampus. There is also increasing evidence supporting the idea that ethanol sensitivity of native BK channel results from differences in BK subunit composition, the proteolipid microenvironment, and molecular determinants of the channel-forming subunit itself. Moreover, these molecular entities play a substantial role in controlling the temporal component of ethanol-associated neuroadaptations in BK channels. Taken together, these studies suggest that SK and BK channels contribute to ethanol tolerance and adaptive plasticity. [source] Alcohol-Induced Tolerance and Physical Dependence in Mice With Ethanol Insensitive ,1 GABAA ReceptorsALCOHOLISM, Issue 2 2009David F. Werner Background:, Although many people consume alcohol (ethanol), it remains unknown why some become addicted. Elucidating the molecular mechanisms of tolerance and physical dependence (withdrawal) may provide insight into alcohol addiction. While the exact molecular mechanisms of ethanol action are unclear, ,-aminobutyric acid type A receptors (GABAA -Rs) have been extensively implicated in ethanol action. The ,1 GABAA -R subunit is associated with tolerance and physical dependence, but its exact role remains unknown. In this report, we tested the hypothesis that ,1-GABAA -Rs mediate in part these effects of ethanol. Methods:, Ethanol-induced behavioral responses related to tolerance and physical dependence were investigated in knockin (KI) mice that have ethanol-insensitive ,1 GABAA -Rs and wildtype (WT) controls. Acute functional tolerance (AFT) was assessed using the stationary dowel and loss of righting reflex (LORR) assays. Chronic tolerance was assessed on the LORR, fixed speed rotarod, hypothermia, and radiant tail-flick assays following 10 consecutive days of ethanol exposure. Withdrawal-related hyperexcitability was assessed by handling-induced convulsions following 3 cycles of ethanol vapor exposure/withdrawal. Immunoblots were used to assess ,1 protein levels. Results:, Compared with controls, KI mice displayed decreased AFT and chronic tolerance to ethanol-induced motor ataxia, and also displayed heightened ethanol-withdrawal hyperexcitability. No differences between WT and KI mice were seen in other ethanol-induced behavioral measures. Following chronic exposure to ethanol, control mice displayed reductions in ,1 protein levels, but KIs did not. Conclusions:, We conclude that ,1-GABAA -Rs play a role in tolerance to ethanol-induced motor ataxia and withdrawal-related hyperexcitability. However, other aspects of behavioral tolerance and physical dependence do not rely on ,1-containing GABAA -Rs. [source] Effects of the Glucocorticoid Antagonist, Mifepristone, on the Consequences of Withdrawal From Long Term Alcohol ConsumptionALCOHOLISM, Issue 12 2008Catherine Jacquot Background:, Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. Materials and Methods:, The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. Results:, Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. Conclusions:, The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits. [source] Only Male Mice Show Sensitization of Handling-Induced Convulsions Across Repeated Ethanol Withdrawal CyclesALCOHOLISM, Issue 3 2007L.M. Veatch Background: Alcohol abuse, especially when experienced in multiple cycles of chronic abuse and withdrawal, leads to a sensitization of central nervous system hyperexcitability that may culminate in overt expression of seizures. In spite of the growing prevalence of alcohol abuse and dependence in females shown in recent epidemiologic studies, evidence of sexual dimorphism in the expression of alcohol withdrawal-induced seizures and the development of seizure sensitization following multiple cycles of ethanol (EtOH) exposure and withdrawal has not been examined in either animal models or in clinical reports. Methods: Subjects in these experiments were male and female C3H/Hecr mice. The female mice were intact or ovariectomized, with ovariectomized mice receiving 17- , -estradiol or placebo pellets. All mice were exposed to 4 cycles of exposure to 16-hour EtOH vapor, separated by 8-hour withdrawal periods. During each 8-hour withdrawal, hourly assessment of seizure propensity was assessed as handling-induced convulsions. Additional assessments were taken up to 72 hours after the final EtOH withdrawal cycle. Results: Male and female mice showed similar seizure propensity during an initial withdrawal from chronic EtOH. Across subsequent withdrawal cycles, however, male mice exhibited a robust increase in seizure severity beginning with the third withdrawal cycle. In marked contrast, female mice failed to demonstrate sensitization of seizure severity. The lack of seizure sensitization following up to 4 cycles of alcohol exposure and withdrawal could not be explained by hormonal status (presence or absence of estrogen) or by sex differences in blood alcohol levels. Conclusions: Male and female mice exposed to the same number of cycles of EtOH withdrawal demonstrate differences in expression of seizures. Males show the typical sensitization of seizures, or kindling response, which has been reported clinically as well as in animal models, but females do not. The reason for the lack of seizure sensitization in female mice remains to be elucidated, but may be related to sex differences in alcohol effects on excitatory/inhibitory neurotransmission, rather than to hormonal or blood alcohol level differences. [source] Role of Parvalbumin in Estrogen Protection From Ethanol Withdrawal SyndromeALCOHOLISM, Issue 10 2005Mridula Rewal Abstract: Background: Parvalbumin (PA) is a calcium-binding protein that has been implicated in protecting neurons from hyperexcitability by sequestering intracellular calcium. This study examined whether ethanol exposure and/or ethanol withdrawal (EW) alter the levels of PA in a manner that is protected by 17,-estradiol (E2). Methods: Ovariectomized rats implanted with E2 (EW/E2) or oil pellets (EW/Oil) received chronic ethanol (7.5% w/v, 5 weeks) or control dextrin (Dex/Oil and Dex/E2) diets. At 0 hr, 24 hr, and 2 weeks of EW, three brain areas (the cerebellum, hippocampus, and cortex) were prepared for immunoblotting and immunohistological assessment of PA. Results: At 24 hr of EW, the EW/Oil group showed reduced levels of PA protein and PA-positive neurons in the cerebellum and hippocampus compared with the dextrin control and the EW/E2 groups. At 2 weeks of EW, the reduced levels of PA persisted in the cerebellum but recovered toward the control levels in the hippocampus. The cortex showed no change in PA levels in any of the treatment groups. When tested at 24 hr of EW, the magnitude of EW signs inversely correlated with the levels of PA in the cerebellum and hippocampus. Ethanol exposure itself did not affect PA levels. Conclusion: These data suggest that EW, rather than ethanol exposure, reduces PA levels in a manner that is brain region specific and that is protected by estrogen. Disturbed PA homeostasis is hypothesized to play a role in the hyperexcitability of EW signs. [source] Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Australian ShepherdJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005J. GEYER A subpopulation of dogs of the Collie and Australian Shepherd breeds show increased sensitivity to central nervous actions of ivermectin, doramectin, loperamide, and probably several other drugs. The molecular background for this greater sensitivity is a nonsense mutation in the MDR1 efflux pump, which is part of the functional blood,brain barrier and normally limits drug penetration into the brain. This report describes a rapid PCR-based method for detection of this nt230(del4) MDR1 mutation using a small amount of genomic DNA from blood cells. Thereby, homozygous intact, homozygous mutated, and heterozygous mutated MDR1 genotypes can be clearly differentiated by high resolution polyacrylamide gel electrophoresis. Using this diagnostic test two Collies and one Australian Shepherd were screened for the nt230(del4) MDR1 mutation. The Collies had no history of altered drug sensitivity and showed homozygous intact and heterozygous mutated MDR1 alleles, respectively. However, the Australian Shepherd developed clear signs of neurotoxicity including ataxia, crawling, acoustic and tactile hyperexcitability, and miosis after a single dose of moxidectin (400 ,g/kg). For this dog two mutated MDR1 alleles were detected. This report describes for the first time moxidectin neurotoxicosis in a dog with a homozygous MDR1 mutation. [source] Action-induced clonus mimicking tremorMOVEMENT DISORDERS, Issue 2 2008Valérie Fraix MD Abstract Action tremor has been described in cerebellar, task-specific, dystonic, or Holmes tremor. We report 2 patients who developed unilateral kinetic or isometric action tremor of the upper extremity, following cervical spondylotic myelopathy and capsular ischemic stroke. Slight motor weakness and spasticity with exaggerated tendon jerks and passive stretch-induced clonus were present on the same limb. The central motor pathways lesions might have been responsible for a hyperexcitability of the stretch-reflex arc and an enhancement of the coactivation of skeletal muscles through a loss of the descending or segmental control of the spinal reflexes. The unusual topography of the symptoms, their occurrence during motion, and the similar frequency of the passive clonus and the action tremor, led us to hypothesize that both patients had prolonged action-induced clonus, mimicking action tremor. Lesions of the central motor pathways lesions might be responsible for action tremor under certain conditions © 2007 Movement Disorder Society [source] | |||||||||||||