1,721,172 research outputs found
The Role of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Pathophysiology of Absence Epilepsy
No full textHyperpolarization-activated cyclic nucleotide-gated (HCN) channels participate in pacemaker currents, modulating the funny current (I[f]) in cardiac cells and the hyperpolarization-activated current (I[h]) in neurons. Depending on the neuronal and synaptic localization, HCN channels regulate synaptic integration, long-term potentiation, synaptic transmission, and resting membrane potential. In summary, it contributes to the electrical activity between the excitatory and inhibitory stimuli through its shunting effect. Several second messengers modulate I(h) currents in the synapses by changing voltage-dependent activation kinetics. I(h) currents are being investigated in numerous central nervous system disorders, including epilepsy. On one hand, it is well known that I(h) currents lead to synchronized oscillations in the rhythmic burst mode in thalamocortical neurons underlying the pathophysiology of absence epilepsy. However, much of the evidence is contradictory. Therefore, it is important to understand the dynamic relationship of HCN channels within the oscillatory networks to determine the regional queerness of I(h), and we need further investigation to determine if upregulation or downregulation of I(h) is needed in order to suppress seizure activity
Are Absence and Limbic Seizures Mutually Exclusive?: An Experimental Approach to Enigmatic Clinical Concept
No full textThe impressive advances in the several disciplines including neurophysiology, molecular biology, neuroimmunology, neurogenetics, neuroimaging, and neuropharmacology of epilepsies have been stimulating a mutual interaction among basic scientists, clinicians, and professionals from other disciplines, leading to the identification of clinical questions and then the design of basic science paradigms to test enigmatic clinical issues. Based on a clinical observation that the coexistence of genetic (idiopathic) generalized typical absence and mesial temporal lobe epilepsy in the same patient is extremely rare and debatable, we addressed the rare coexistence in the same individual, designed an experimental approach to test the validity of this clinical concept and to study the underlying mechanisms involved. Here we presented evidence of a mutual cross-interaction in the circuits involved in typical absence and temporal lobe epilepsy. This article delineates a phenomenological picture and comprehends a theoretical understanding of a mutual cross-interaction in typical absence as a representative of genetic generalized epilepsies and limbic epilepsy in which seizures often start from the mesial temporal lobe
Electroencephalographic differences between WAG/Rij and GAERS rat models of absence epilepsy
No full textThe inbred Wistar Albino Glaxo Rats from Rijswijk (WAG/Rij) and the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are well-validated genetic models of absence epilepsy. Although they share similar characteristics including the spike-and-wave discharges (SWDs) in the EEG, some differences have been reported between both strains. This study aimed a systematic and detailed comparison of the SWD patterns of both strains in terms of the intensity, frequency and waveform morphology of the discharges by using exactly the same measurement and analysis techniques. The number, cumulative total duration and mean duration of SWDs were significantly higher in GAERS compared to WAG/Rij, while the discharge frequency was higher in the WAG/Rij. Furthermore, SWDs spectra and average SWD waveforms indicated that a single cycle of the SWD contains more energy in faster components such as spike and late positive transient in the GAERS. Additionally, WAG/Rij exhibited a significantly higher power between 8 and 14 Hz during the pre-SWD period. These clear phenomenological differences in the EEGs of both animal models suggest that these variables may represent basic phenotypic features of SWDs that should be sought after in the future studies that explore the genetic and molecular basis of absence epilepsy. (C) 2009 Elsevier B.V. All rights reserved
Animal models of absence epilepsies: What do they model and do sex and sex hormones matter?
No full textWhile epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model (also with a higher prevalence in males) and the Gabral deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17 beta-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABA(A) receptors (GABA(A)Rs). Neurosteroids also modulate the expression of GABA(A)R containing the gamma 2, alpha 4, and delta subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states. (C) 2014 Elsevier Inc All rights reserved
Do the quantitative relationships of synaptic junctions and terminals in the thalamus of genetic absence epilepsy rats from Strasbourg (GAERS) differ from those in normal control Wistar rats
No full textAbnormal functional properties of the thalamocortical connections were reported in the absence of epilepsy. The present study compares the ratios of terminals (`RL'-round vesicles, large terminals, 'RS'-round vesicles, small terminals and 'F'-flattened vesicles) and synapse in three first-order (ventrobasal, lateral geniculate and anteroventral) and in three higher-order (posterior, lateral posterior and mediodorsal) thalamic nuclei of genetic absence epilepsy rats from Strasbourg (GAERS) with our earlier quantitative studies of normal Wistar rats to show whether quantitative differences were present in GAERS as compared to Wistar rat. Rats were perfused transcardially, the brains were removed and cut as 300 lmcoronal sections. Parts of the six thalamic nuclei were removed for routine electron microscopy and GABA immunocytochemistry. Twenty photographs from each section at 20,0009 magnification were taken, and the terminals were identified as RL, RS or F. (1) In normal Wistar rats (as in cats), the proportion of driver terminals (RL) and synapses is lower in higherorder than in first-order thalamic nuclei, but this difference is not present in GAERS animals. (2) The proportions of RS terminals and synapses for each thalamic nucleus showed no significant differences between GAERS and Wistar rats for any of the thalamic nuclei. (3) In GAERS, the proportion of inhibitory F terminals and synapses was significantly high in the VB and low in the LP thalamic nucleus. These abnormal ratios in the GAERS may be the cause of the spike-and-wave discharges of absence seizures or may represent a compensatory response of the thalamocortical circuitry to the absence seizures
Synaptic organization of the rat thalamus: a quantitative study
No full textFirst-order thalamic nuclei receive driving afferents from ascending pathways and transmit processed information to the cortex. Higher-order thalamic nuclei receive driver messages from layer 5 of cortex and transmit information from one cortical area to the other. The different types of axon terminals RL (round vesicles, large terminals), RS (round vesicles, small terminals) and F (flattened vesicles) and their synaptic junctions have been here compared in three first-order (ventrobasal, lateral geniculate and anteroventral) and three higher-order (posterior, lateral posterior and mediodorsal) thalamic nuclei of the rat. In the present study, the higher-order relays differ from first-order relays as in the cat, in having fewer driver terminals (RL) and synapses than do the first-order relays. However, the F terminals showed opposite ratios in the first versus higher-order thalamic nuclei. The majority of the terminals in all thalamic nuclei studied were RS terminals. The area measurements of the three types of terminals and synaptic lengths showed no significant differences between first and higher-order nuclei. The driver inputs represent the minority and the modulatory inputs represent the majority of the terminals and synapses in all thalamic nuclei. In conclusion, there is a relative paucity of driver inputs, whereas modulatory inputs establish more numerous synapses to achieve finer modulation
A developmental study of glutamatergic neuron populations in the ventrobasal and the lateral geniculate nucleus of the thalamus: Comparing Genetic Absence Rats from Strasbourg (GAERS) and normal control wistar rats
No full textAn imbalance of GABAergic inhibition and glutamatergic excitation is suspected to be the cause of absence epileptic seizures. Absence seizures are known to be generated in thalamocortical circuitry. In the present study we used light microscopy immunohistochemistry to quantify the density of glutamate+ve neurons at two developmental stages (P10 and P60) in two thalamic nuclei, the ventrobasal (VB) and lateral geniculate nucleus (LGN) in Wistar rats and compared the results with similar data obtained from genetic absence epilepsy rats from Strasbourg (GAERS). Rats were perfused transcardially with glutaraldehyde and paraformaldehyde fixative, then samples from VB and LGN were removed from each animal and sectioned. The glutamatergic neurons were labelled using light-microscopic glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in VB and LGN of GAERS and Wistar rats. The data were statistically analyzed. The distribution of the glutamate+ve neurons in the VB thalamic nucleus showed a significant reduction in the neuronal profiles per unit thalamic area from P10 to P60 in both Wistar and GAERS. The decrease was greater in the GAERS compared to the Wistar animals. However, in the LGN no reduction was observed either in the Wistar or in the GAERS. Comparing the density of glutamate+ve neurons in the VB thalamic nucleus of P10 of Wistar animals with of P10 GAERS showed statistically significant greater densities of these neurons in GAERS than in the Wistar rats. However no significant difference was present at P60 between the Wistar and GAERS animals. The disproportional decrease in GAERS may be related to the onset of absence seizures or may be related to neurogenesis of absence epilepsy. (C) 2016 ISDN. Published by Elsevier Ltd. All rights reserved
Comparing glutamatergic neuron population in the mediodorsal thalamic nucleus of genetic absence epilepsy rats from strasbourg (GAERS) and normal control Wistar rats
No full textAn imbalance between GABAergic inhibition and glutamatergic excitation is suspected to play a role in the genesis of epileptic processes. In the present study we quantified the number of glutamate+ve neurons in the mediodorsal thalamic nucleus (MD) of genetic absence epilepsy rats from Strasbourg (GAERS) and compared these with values for normal Wistar rats. The MD thalamic nucleus was removed from each animal and the glutamatergic neurons were labelled using light-microscopy glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in the MD thalamic nucleus of GAERS and Wistar rats. The data were statistically analyzed. In the Wistar animals glutamate+ve neurons formed 89% and in GAERS 92.3% of the total neurons in 1000 mu m(3) of MD thalamic nucleus. In GAERS glutamate+ve neurons showed statistically significant increase in the MD thalamic nucleus compared to Wistar animals. In Wistar animals the glutamate-ve neurons formed 11% and in GAERS 7.7% of the total neurons in 1000 mu m(3) of MD thalamic. No significant difference was observed in glutamate ye neurons between the two strains. The average diameter of glutamate-ve neurons showed no significance, while glutamate-ve neurons were significant between the two strains. The results of the present study, on genetic absence epilepsy model, GAERS, confirms the role of MD thalamic nucleus in chemically induced absence epilepsy. (C) 2016 Elsevier B.V. All rights reserved
Immunocytochemical analysis of glutamate and GABA in hippocampus of genetic absence epilepsy rats (GAERS)
No full textIn the present study, we used an immunocytochemical technique at the electron microscopic level to determine if there are changes in the glutamate and GABA neurotransmitter content of the hippocampus of genetic absence epilepsy rats from Strasbourg (GAERS). We also investigated if there was mossy fiber reorganization. After perfusion fixation, brains were removed and cryostat sections were stained according to the neo-Timm's procedure. High-resolution electron microscopy was used for ultrastructural examination of the hippocampus of GAERS and non-epileptic control Wistar animals. For ultrastructural and immunocytochemical studies, ultrathin-cut sections were obtained and immunolabeled with anti-glutamate and anti-GABA antibodies. The number of gold particles per nerve terminal was counted and the area of the nerve terminal was determined using the program NIH Image Analysis. No mossy fiber sprouting was detected in the hippocampus of GAERS. GABA and glutamate immunoreactivity were observed in the mossy fiber terminals of both the control and GAERS groups. Glutamate density in the CA3 region of GAERS hippocampus was found to be significantly increased compared to the control group. However, there was no difference in the GABA density of nerve terminals and in areas of GABAergic and mossy terminals between GAERS and the control group. The difference in glutamate level may merely be due to strain differences between the GAERS strain and the original Wistar strain or it is also possible that it appears after seizures have started
The Role of Rho/Rho-Kinase Pathway in the Pathophysiology of Absence Epilepsy
No full textObjectives: Rho/Rho-kinase (ROCK) signaling has been shown to contribute to neuroinflammation, epileptogenesis, and seizures in convulsive-type epilepsy models. However, this pathway has not been investigated in the pathophysiology of absence epilepsy. The aim of this study was to investigate ROCK activity in brain regions involved in spike-and-wave discharge (SWD) generation and the effects of the Rho-kinase inhibitor, Y-27632, on ROCK activity in genetic absence epilepsy rats from Strasburg (GAERS). Methods: ROCK activity in the somatosensorial cortex, hippocampus, and thalamus was measured using an enzyme-linked immunosorbent assay (ELISA). An intracerebroventricular (i.c.v.) injection of Y-27632 was administered at a dose of 20 nmol/5 mu l and changes in ROCK activity were assessed. To evaluate the effect of Y-27632 on SWDs, i.c.v. 20 nmol and 60 nmol doses of Y-27632 were administered to the GAERS subjects and electroencephalography was performed. Results: ROCK activity was elevated in the somatosensory cortex in the GAERS study subjects, and the Rho-kinase enzyme inhibitor, Y-27632, suppressed this increase. In addition, Y-27632 significantly reduced the total and mean duration of SWDs compared with the control group. Conclusion: The findings indicate that the Rho-kinase pathway may play a role in the generation of absence seizures, and that the suppressive effect of Y-27632 on SWDs may be a potential therapeutic target for this anti-absent effect
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