RESUMEN
OBJECTIVE: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a genetic model, derived from Wistar rats by selective breeding. In all previous studies, GAERS were compared to their paired selected strain not expressing spike-and-wave discharges (SWDs), namely nonepileptic controls (NECs). Because the occurrence/absence of SWDs is of polygenic origin, some other traits could have been selected along with occurrence/absence of SWDs. Therefore, we explored the importance of using a second control group consisting in Wistar rats, the strain of origin of GAERS, in addition to NECs, on locomotion and anxiety in GAERS. METHODS: A test battery encompassing home-cage, open-field, beam-walking and elevated plus-maze evaluations was used. In addition, stereologic analyses were performed to assess the volume of thalamus, amygdala, and hippocampus. The occurrence/absence of SWDs was determined in all three strains by electroencephalography (EEG) recording. RESULTS: When compared to NECs and Wistars, GAERS displayed lower exploratory activity and fastened habituation to novelty. In the plus-maze, scores of GAERS and Wistars were similar, but NECs appeared significantly less anxious (possibly in association with increased amygdala volume); evidence for weaker anxiety in NECs was also found in the open-field evaluation. The volumetric study revealed increased thalamic volume in GAERS compared to both control groups. SWDs were present in all GAERS and in 80% of Wistars. SIGNIFICANCE: Compared to the original Wistar strain as an additional control group, the selective breeding that generated the GAERS has no incidence on anxiety-related behavior, conversely to the selection of SWD suppression in NECs, in which anxiety is attenuated. These findings point to the importance of using a second control group composed of Wistar rats in studies characterizing the behavioral profile of GAERS. Thereby, possible confusions between occurrence/absence of SWDs and other features that come along with selection and/or differential brain development induced by the genetic mutations are reduced.
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Ansiedad/etiología , Epilepsia Tipo Ausencia/complicaciones , Epilepsia Tipo Ausencia/genética , Trastornos Neurológicos de la Marcha/etiología , Análisis de Varianza , Animales , Encéfalo/patología , Ondas Encefálicas/fisiología , Modelos Animales de Enfermedad , Electroencefalografía , Conducta Exploratoria/fisiología , Locomoción/genética , Masculino , Aprendizaje por Laberinto , Desempeño Psicomotor/fisiología , Ratas , Ratas Mutantes , Ratas WistarRESUMEN
OBJECTIVE: Temporal lobe epilepsy is a relatively frequent, invalidating, and often refractory neurologic disorder. It is associated with cognitive impairments that affect memory and executive functions. In the rat lithium-pilocarpine temporal lobe epilepsy model, memory impairment and anxiety disorder are classically reported. Here we evaluated sustained visual attention in this model of epilepsy, a function not frequently explored. METHODS: Thirty-five Sprague-Dawley rats were subjected to lithium-pilocarpine status epilepticus. Twenty of them received a carisbamate treatment for 7 days, starting 1 h after status epilepticus onset. Twelve controls received lithium and saline. Five months later, attention was assessed in the five-choice serial reaction time task, a task that tests visual attention and inhibitory control (impulsivity/compulsivity). Neuronal counting was performed in brain regions of interest to the functions studied (hippocampus, prefrontal cortex, nucleus basalis magnocellularis, and pedunculopontine tegmental nucleus). RESULTS: Lithium-pilocarpine rats developed motor seizures. When they were able to learn the task, they exhibited attention impairment and a tendency toward impulsivity and compulsivity. These disturbances occurred in the absence of neuronal loss in structures classically related to attentional performance, although they seemed to better correlate with neuronal loss in hippocampus. Globally, rats that received carisbamate and developed motor seizures were as impaired as untreated rats, whereas those that did not develop overt motor seizures performed like controls, despite evidence for hippocampal damage. SIGNIFICANCE: This study shows that attention deficits reported by patients with temporal lobe epilepsy can be observed in the lithium-pilocarpine model. Carisbamate prevents the occurrence of motor seizures, attention impairment, impulsivity, and compulsivity in a subpopulation of neuroprotected rats.
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Atención , Modelos Animales de Enfermedad , Epilepsia Parcial Compleja/psicología , Epilepsia del Lóbulo Temporal/psicología , Función Ejecutiva , Estado Epiléptico/psicología , Animales , Anticonvulsivantes/farmacología , Atención/efectos de los fármacos , Atención/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Mapeo Encefálico , Carbamatos/farmacología , Recuento de Células , Epilepsia Parcial Compleja/inducido químicamente , Epilepsia Parcial Compleja/fisiopatología , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/fisiopatología , Función Ejecutiva/efectos de los fármacos , Función Ejecutiva/fisiología , Inhibición Psicológica , Carbonato de Litio , Neuronas/efectos de los fármacos , Neuronas/fisiología , Reconocimiento Visual de Modelos/efectos de los fármacos , Reconocimiento Visual de Modelos/fisiología , Pilocarpina , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Aprendizaje Seriado/efectos de los fármacos , Aprendizaje Seriado/fisiología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatologíaRESUMEN
PURPOSE: Administration of carisbamate during status epilepticus (SE) prevents the occurrence of motor seizures in the lithium-pilocarpine model and leads in a subpopulation of rats to spike-and-wave discharges characteristic of absence epilepsy. Widespread neuroprotection accompanied this change in seizure expression. To assess whether these carisbamate-induced changes affected comorbidity, we used a large battery of behavioral tests in rats that had developed temporal lobe or absence-like seizures. METHODS: Lithium-pilocarpine or saline was administered to 60 adult rats. Carisbamate (90 mg/kg) or diazepam and saline was given 1 h after SE onset, and repeated 8 h later and twice daily over 6 more days. Rats were video-monitored for 2 months. Subsequently, locomotor activity, anxiety, and various types of memory were assessed. KEY FINDINGS: In rats with motor seizures, treated or not with carisbamate, all features of behavior were impaired compared to controls. Rats exhibiting absence-like seizures after carisbamate treatment behaved as controls in all paradigms tested along with widespread neuroprotection. SIGNIFICANCE: Carisbamate treatment leading to absence-like instead of temporal lobe seizures impressively prevented behavioral comorbidities reported by patients with epilepsy as the most disabling.
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Anticonvulsivantes/administración & dosificación , Conducta Animal/efectos de los fármacos , Carbamatos/administración & dosificación , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/fisiopatología , Animales , Antipsicóticos/toxicidad , Encéfalo/patología , Recuento de Células , Modelos Animales de Enfermedad , Litio/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Fibras Musgosas del Hipocampo/efectos de los fármacos , Fibras Musgosas del Hipocampo/patología , Agonistas Muscarínicos/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fosfopiruvato Hidratasa/metabolismo , Pilocarpina/toxicidad , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , Estado Epiléptico/patología , Percepción Visual/efectos de los fármacosRESUMEN
We conducted a longitudinal online study to examine attenuated psychotic symptoms (APS) over time in a sample of locked-down individuals. We used (i) questionnaires and (ii) the automatic analysis of the emotional content of narratives. Participants (N = 162) were recruited to complete an online survey 4 times between March and June 2020 (T1, T2, T3, T4). T1 completion coincided with the beginning of the lockdown, and T4 with the pandemic trough. Depression, anxiety, and stress were assessed with the DASS-42 and APS with the PQ-16. Psychosocial data such as the feeling of loneliness and social network size were also collected. The participants wrote daily narratives during the lockdown period. Anxiety and APS were the highest at T1 and decreased over time. APS and APS-associated distress were correlated with the DASS-42 at all times. APS arose acutely at the beginning of the pandemic, despite participants being socio-economically advantaged, and were related with negative emotions.
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Longitudinal studies on patients for schizophrenia suggest that functional brain perturbations precede the onset of symptoms. Rats with a neonatal ventral hippocampal lesion (NVHL) are considered as a heuristic neurodevelopmental model of schizophrenia. We characterized basal metabolic changes observed in NVHL rats before and after the age when known behavioral alterations have been reported. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD7). We measured local cerebral metabolic rates for glucose (LCMRglc) by the quantitative autoradiographic [(14)C]2-deoxyglucose technique at pre- (PD21) and postpubertal (PD42) ages when NVHL rats do not express abnormal dopamine related behaviors, and at adulthood (PD70). We observed a widespread increase in LCMRglcs in PD21 NVHL indicative of an ongoing intense reorganization of the brain while at PD42, increases were less extended. At PD70, changes in glucose metabolism were restricted to specific systems, such as the auditory system, the cerebellum, the serotonergic median raphe, and median septum. These data show in a heuristic animal model of schizophrenia that functional metabolic changes within the brain could precede the onset of dopamine-related behavioral alterations and lead to a distinct ensemble of functional changes in adulthood in systems that may be relevant to schizophrenia.
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Encéfalo/metabolismo , Hipocampo/lesiones , Esquizofrenia/metabolismo , Animales , Animales Recién Nacidos , Autorradiografía , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hipocampo/metabolismo , Masculino , Ratas , Esquizofrenia/etiología , Esquizofrenia/fisiopatologíaRESUMEN
PURPOSE: Although the number of antiepileptic drugs (AEDs) is increasing, none displays neuroprotective or antiepileptogenic properties that could prevent status epilepticus (SE)-induced drug-resistant epilepsy. Ketogenic diet (KD) and calorie restriction (CR) are proposed as alternative treatments in epilepsy. Our goal was to assess the neuroprotective or antiepileptogenic effect of these diets in a well-characterized model of mesial temporal lobe epilepsy following initial SE induced by lithium-pilocarpine in adult rats. METHODS: Seventy-five P50 male Wistar rats were fed a specific diet: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), or hypocalorie ketogenic (HK). Rats were subjected to lithium-pilocarpine SE, except six NC to constitute a control group for histology (C). Four rats per group were implanted with epidural electrodes to record electroencephalography (EEG) during SE and the next six following days. From the seventh day, the animals were video-recorded 10 h daily to determine latency to epilepsy onset. Neuronal loss in hippocampus and parahippocampal cortices was analyzed 1 month after the first spontaneous seizure. RESULTS: After lithium-pilocarpine injection, neither KD nor CR modified SE features or latency to epilepsy. In hippocampal layers, KD or CR exhibited a neuroprotective potential without cooperative effect. Parahippocampal cortices were not protected by the diets. CONCLUSION: The antiepileptic effect of KD and/or CR is overwhelmed by lithium-pilocarpine injection. The isolated protection of hippocampal layers induced by KD or CR or their association failed to modify the course of epileptogenesis.
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Anticonvulsivantes/farmacología , Restricción Calórica/métodos , Dieta Cetogénica/métodos , Epilepsia del Lóbulo Temporal/prevención & control , Hipocampo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Carbohidratos de la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Electroencefalografía/efectos de los fármacos , Electroencefalografía/estadística & datos numéricos , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Humanos , Cloruro de Litio , Masculino , Pilocarpina , Ratas , Ratas Wistar , Estado Epiléptico/inducido químicamenteRESUMEN
Learning and imitating a complex motor action requires to visually follow complex movements, but conscious perception seems too slow for such tasks. Recent findings suggest that visual perception has a higher temporal resolution at an unconscious than at a conscious level. Here we investigate whether high-temporal resolution in visual perception relies on prediction mechanisms and attention shifts based on recently experienced sequences of visual information. To that aim we explore sequential effects during four different simultaneity/asynchrony discrimination tasks. Two stimuli are displayed on each trial with varying stimulus onset asynchronies (SOA). Subjects decide whether the stimuli are simultaneous or asynchronous and give manual responses. The main finding is an advantage for different-order over same-order trials, when subjects decided that stimuli had been simultaneous on Trial t - 1 , and when Trial t is with an SOA slightly larger than Trial t - 1, or equivalent. The advantage for different-order trials disappears when the stimuli change eccentricity but not direction between trials (Experiment 2), and persists with stimuli displayed in the centre and unlikely to elicit a sense of direction (Experiment 4). It is still observed when asynchronies on Trial t - 1 are small and undetected (Experiment 3). The findings can be explained by an attention shift that is precisely planned in time and space and that incidentally allows subjects to detect an isolated stimulus on the screen, thus helping them to detect an asynchrony.
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Estado de Conciencia , Percepción del Tiempo , Percepción Visual , Atención , Humanos , Tiempo de Reacción , Visión OcularRESUMEN
Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.
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Regulación de la Expresión Génica/fisiología , Hipocampo/lesiones , Hipocampo/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Estimulación Acústica/efectos adversos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Apomorfina/farmacología , Calbindina 2 , Calbindinas , Agonistas de Dopamina/farmacología , Electroencefalografía/métodos , Femenino , Antagonistas del GABA/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Hipocampo/efectos de los fármacos , Ácido Iboténico/toxicidad , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Parvalbúminas/metabolismo , Pentilenotetrazol/farmacología , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Proteína G de Unión al Calcio S100/metabolismo , Convulsiones/inducido químicamente , Transmisión Sináptica/efectos de los fármacosRESUMEN
PURPOSE: Genetic absence epilepsy rats from Strasbourg (GAERS) are resistant to the progression of kindling seizures. We studied local cerebral blood flow (LCBF) changes in brain regions involved in seizures in both GAERS and nonepileptic rats (NEC) to map the differences that may be related to the resistance to kindling. METHODS: Electrodes were implanted in the amygdala of adult NEC and GAERS male rats, which were stimulated to reach stage 2. Quantitative autoradiographic measurements of LCBF were performed by the [(14)C]-iodoantipyrine ([(14)C]IAP) autoradiographic technique allowing the precise mapping of regional perfusion changes. LCBF rates were measured bilaterally in 43 brain regions. The tracer infusion lasted for 60 s and started at 15 s before seizure induction. RESULTS: Rates of LCBF increased in stimulated GAERS and NEC groups compared to nonstimulated controls. The LCBF increase in stimulated GAERS was larger and more widespread than that observed in stimulated NEC. The LCBF increase in the somatosensory cortex, ventrobasal and anterior thalamic nuclei, hypothalamus, subthalamic nucleus, piriform, entorhinal and perirhinal cortex, amygdala, CA2 region of hippocampus, and substantia nigra was statistically significantly larger in stimulated GAERS compared to stimulated NEC rats. CONCLUSION: The results show that more brain regions are activated by kindling stimulation in GAERS. This widespread activation in GAERS involves the somatosensory cortex and thalamus, which are both known to be involved in the expression of absence seizures as well as numerous limbic regions thought not to play a role in the expression of absence seizures, suggesting an interaction between corticothalamocortical and limbic circuitries.
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Encéfalo/irrigación sanguínea , Epilepsia Tipo Ausencia/genética , Excitación Neurológica/fisiología , Animales , Circulación Cerebrovascular/fisiología , RatasRESUMEN
The susceptibility of rats with genetically inherited epilepsy to the genesis and consequences of secondary temporal lobe epilepsy is unknown. Here, we induced lithium-pilocarpine status epilepticus (SE) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) or in Wistar audiogenic sensitive (AS) rats. Wistar AS needed less pilocarpine than GAERS and Non-Epileptic Rats (NERs) to develop SE. Sixty six, 40 and 5% of Wistar AS, GAERS and NERs, respectively, died within 24 h after SE. In GAERS, SE prevented the occurrence of absence seizures for 5 days. Thereafter a limited number of absence seizures with low amplitude and short duration were recorded. Wistar AS developed limbic epilepsy within 9 days after SE while GAERS and NERs needed 36-39 days to develop spontaneous motor seizures. Neuronal loss consecutive to SE was similar in the three strains and particularly marked in limbic forebrain and parahippocampal cortices. In conclusion, the development of focal limbic epilepsy in GAERS largely impairs the expression of absence seizures. The genetic background underlying the expression of audiogenic seizures sensitizes strongly the rats to a further insult and compromises their survival.
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Epilepsia Tipo Ausencia/genética , Epilepsia Refleja/genética , Epilepsia del Lóbulo Temporal/genética , Epilepsia/genética , Predisposición Genética a la Enfermedad/genética , Estado Epiléptico/genética , Animales , Antimaníacos/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Electroencefalografía , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Epilepsia Tipo Ausencia/fisiopatología , Epilepsia Refleja/inducido químicamente , Epilepsia Refleja/fisiopatología , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/fisiopatología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiopatología , Compuestos de Litio/farmacología , Masculino , Agonistas Muscarínicos/farmacología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Giro Parahipocampal/efectos de los fármacos , Giro Parahipocampal/fisiopatología , Pilocarpina/farmacología , Ratas , Ratas Mutantes , Ratas Wistar , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatologíaRESUMEN
In mice, deletion of the STOP protein leads to subtle anatomic changes and induces depleted synaptic vesicle pools, impaired synaptic plasticity, hyperdopaminergy, and major behavioral disorders alleviated by neuroleptics, hence leading to a schizophrenic-like phenotype. In this study, we applied the quantitative autoradiographic [(14)C]2-deoxyglucose technique to study to what extent the basal rate of cerebral glucose utilization in STOP-knockout (STOP-KO) mice occurs in regions where metabolic changes have been reported in schizophrenic patients. Studies were performed on wild-type, heterozygous, and homozygous STOP-KO mice (7-8 per group). Mice were implanted with femoral artery and vein catheters, and cerebral glucose utilization was quantified over 45 min. Compared with that in wild-type mice, glucose utilization in STOP-KO mice was significantly increased in the olfactory cortex, ventromedial and anterolateral hypothalamus, ventral tegmental area, and substantia nigra pars compacta. Nonsignificant increases, ranging between 9% and 19%, were recorded in the whole auditory system, CA1 pyramidal cell layer, and dorsal raphe. Glucose utilization was also significantly increased in heterozygous mice compared with that in wild-type mice in olfactory cortex. These data might reflect hyperdopaminergic activity, olfactory deficits, and sleep disturbances in STOP-KO mice that have also been reported in schizophrenic patients.
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Encéfalo/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Animales , Autorradiografía , Glucosa/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
The regular use of cannabis generates pronounced cognitive disorders, especially in users who begin before the age of 15-16. However, less is known about the impact of regular cannabis on visual function, especially in the case of early onset. Cannabinoid receptors (CB1) are expressed in areas of the visual system, like the thalamus and primary cortex, which might originate sensory disorders. Hence, we measured contrast sensitivity (CS) in three groups, i.e. cannabis users with late onset of cannabis use (after 16 years old), cannabis users with early onset". We used a constant method which allowed us to control for biased responses. Stimuli were presented at high and low spatial frequencies and in both static and dynamic conditions (8Hz). As contrast sensitivity is measured behaviorally based on an explicit response and could thus be impacted by attentional or vigilance disorders, participants' attention and vigilance were carefully monitored by means of the D2 test, CPT-AX for attention and pupillography for vigilance. Cannabis users with early onset were significantly impaired only at low spatial frequency. This effect was independent of response bias, vigilance and attention. These results show for the first time that early cannabis use impacts contrast sensitivity at low spatial frequency.
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Sensibilidad de Contraste/fisiología , Fumar Marihuana/fisiopatología , Trastornos de la Percepción/etiología , Adulto , Edad de Inicio , Análisis de Varianza , Atención/fisiología , Estudios de Casos y Controles , Femenino , Humanos , Conducta Impulsiva/fisiología , Masculino , Trastornos de la Percepción/fisiopatología , Estimulación Luminosa , Pupila/fisiología , Adulto JovenRESUMEN
Glutamate excitotoxicity has been involved in the pathophysiology of epilepsy. Normal functioning of glutamate transporters clears the synaptically released glutamate to prevent excitotoxic neuronal death. Using densitometric immunohistochemical analysis, we examined the temporal expression of the neuronal glutamate transporter (EAAC1) in the lithium-pilocarpine rat model of temporal lobe epilepsy. During the acute period of lithium-pilocarpine-induced status epilepticus, EAAC1 transporter expression increased in the pyramidal neurons of cornus ammonis (CA)1, CA2 and CA3 (fields of the hippocampus), in dentate gyrus (DG) granule cells and in olfactory tubercle (Tu). During the latent period, EAAC1 expression was strongly expressed in the DG granular and molecular layers, Tu, cerebral cortex and septum, and went back to control levels in CA1, CA2 and CA3 layers. The overexpression of EAAC1 occurred mainly in structures prone to develop Fluoro-Jade-B-positive degenerating neurons. It is, however, not clear to what extent the overexpression of EAAC1 contributes to epileptogenesis and in which area it may represent a preventive or compensatory or response to injury.
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Epilepsia del Lóbulo Temporal/metabolismo , Transportador 3 de Aminoácidos Excitadores/biosíntesis , Cloruro de Litio , Pilocarpina , Animales , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/patología , Fluoresceínas , Inmunohistoquímica , Degeneración Nerviosa , Compuestos Orgánicos , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatologíaRESUMEN
Lithium-pilocarpine induces status epilepticus (SE), leading to extensive damage and spontaneous recurrent seizures (SRS). Neuroprotective and antiepileptogenic effects of topiramate (TPM) associated with diazepam (DZP) were investigated in this model. SE was induced by LiCl and pilocarpine. TPM (10, 30 or 60 mg/kg) was injected at the onset of SE and 10h later and DZP (2.5 and 1.25mg/kg) at 2 and 10h after SE. TPM treatment was continued twice daily for 6 days. Other rats received two injections of DZP on the day of SE. Cell counting was performed on thionine-stained sections 14 days after SE and after 2 months of epilepsy. Occurrence and frequency of SRS were video-recorded. The MRI T2-weighted signal was quantified in hippocampus and ventral cortices. DZP-TPM treatment induced partial neuroprotection in CA1 and hilus, and tended to increase the percentage of rats with protected neurons in layer III/IV of the ventral entorhinal cortex. The latency to and frequency of SRS were not modified by DZP-TPM. T2-weighted signal was decreased in hippocampus 3 days after SE at all TPM doses and in ventral hippocampus after epilepsy onset. In conclusion, although DZP-TPM treatment was able to partially protect two areas critical for epileptogenesis, the hippocampus and ventral entorhinal cortex, it was not sufficient to prevent epileptogenesis.
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Anticonvulsivantes/uso terapéutico , Diazepam/uso terapéutico , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Fructosa/análogos & derivados , Hipocampo/efectos de los fármacos , Estado Epiléptico/tratamiento farmacológico , Animales , Anticonvulsivantes/farmacología , Diazepam/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Electroencefalografía/efectos de los fármacos , Epilepsia del Lóbulo Temporal/inducido químicamente , Fructosa/farmacología , Fructosa/uso terapéutico , Litio , Imagen por Resonancia Magnética , Masculino , Pilocarpina , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , TopiramatoRESUMEN
RATIONALE: Measurement of local cerebral blood flow (LCBF) is routinely used to locate the areas involved in the generation and spread of seizures in epileptic patients. Since the spatial distribution and extent of ictal LCBF depends on the epileptogenic network, but also on the timing of injection of tracer, we used a rat model of amygdala kindled seizures to follow time-dependent changes in the distribution of seizure-induced LCBF changes. METHODS: Rats were implanted with a left amygdala electrode and were stimulated until reaching stage 1. LCBF was measured by the quantitative [14C]iodoantipyrine autoradiographic technique. The tracer was injected either at 15 s before seizure induction (early ictal) or simultaneously with the amygdala stimulation (ictal) in rats undergoing a stage 0 or 1 seizure. RESULTS: During stage 0 seizures, LCBF rates increased significantly ipsilaterally in medial and central amygdala and substantia nigra. During stage 1 seizures, LCBF increased unilaterally in amygdala, piriform cortex, substantia nigra, ventral tegmental area and cerebellum and bilaterally in several limbic and subcortical structures, excepted in hippocampus and pallidum. When pooling stages 0 and 1 but considering only tracer injection time, discrete LCBF changes occurred ipsilaterally in amygdala and substantia nigra at early ictal time. At true ictal time, significant changes occurred in several subcortical structures bilaterally while limbic structures displayed more localized and lateralized changes. CONCLUSION: LCBF mapping appears unable to identify in rats the ictal onset zone of clinically significant amygdala-triggered seizures (stage 1), while the study of sub-clinical seizures (stage 0) allowed to correctly locate the amygdala onset of the seizures within the limbic network. Compared to human SPECT studies, this work confirms that some ictal hyperperfused areas belong to the spreading network rather than to the epileptogenic zone. The spatial recruitment of remote subcortical structures could be further investigated to strengthen the rationale of therapeutic stimulation of basal ganglia in drug-resistant epilepsies.
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Circulación Cerebrovascular/fisiología , Epilepsias Parciales/fisiopatología , Convulsiones/fisiopatología , Amígdala del Cerebelo/patología , Animales , Antipirina/administración & dosificación , Antipirina/análogos & derivados , Radioisótopos de Carbono/administración & dosificación , Estimulación Eléctrica , Electrodos , Inductores de Interferón/administración & dosificación , Excitación Neurológica , Masculino , Ratas , Ratas Wistar , Convulsiones/etiología , Factores de TiempoRESUMEN
The influence of caffeine on epileptic seizures remains a matter of debate. Here we tested on Genetic Absence Epilepsy Rats from Strasbourg (GAERS) the consequences of acute and chronic exposure to caffeine on the expression of spike-and-wave discharges (SWDs). Since caffeine is a mixed nonspecific A(1) and A(2A) adenosine receptor antagonist, we measured also the influence of antagonists and agonists of these receptors on SWD expression. GAERS were equipped with four cortical electrodes over the frontoparietal cortex and the cumulated duration and number of SWDs were recorded for 120 min after the injection of increasing doses of caffeine, specific antagonists and agonists of A(1) and A(2A) adenosine receptors. The effects of chronic caffeine were also studied. In GAERS, caffeine dose-dependently reduced the cumulated number and duration of SWDs which almost disappeared after the injection of the two highest doses of caffeine, 5 and 10 mg/kg. Likewise, the A(1) and A(2A) adenosine receptor antagonists led to a dose-dependent reduction of SWD expression while the agonists dose-dependently increased SWD expression. Conversely, the chronic exposure to caffeine via drinking water for 15 days did not influence SWD expression. With the exception of the two highest doses of caffeine that largely enhanced activity, all compounds including low doses of caffeine had no effect on locomotor activity of GAERS. These data show that the acute exposure to low doses of caffeine, or A(1) and A(2A) adenosine receptor antagonists reduces SWD expression in GAERS, independently from any effect on motor activity. The chronic exposure of GAERS to caffeine does not affect the expression of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Cafeína/farmacología , Epilepsia Tipo Ausencia/tratamiento farmacológico , Agonistas Purinérgicos/farmacología , Antagonistas Purinérgicos/farmacología , Animales , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrodos Implantados , Electroencefalografía , Epilepsia Tipo Ausencia/fisiopatología , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatología , Factores de TiempoRESUMEN
The causal relationship between early seizures and subsequent temporal lobe epilepsy has not yet been established. Prospective clinical studies reported that seizures occurring early in life rarely result in hippocampal sclerosis. Likewise, in most experimental models, early seizures occurring before the end of the second postnatal week do not lead to neuronal damage and subsequent epilepsy. In some models, this early event decreases latency sensitivity and threshold to seizures. In the present study, we induced lithium and pilocarpine status epilepticus (SE) in 10-day-old (P10) rats. The goal of this study was to determine whether this early life SE altered the sensitivity to convulsants such as pentylenetetrazol (20 and 25 mg/kg), picrotoxin (2.5 and 4.0 mg/kg) and kainate (5 and 8 mg/kg) during adulthood. The occurrence of electrographic seizures (spike-and-wave discharges, SWD) and/or of behavioral seizures was monitored. There was no difference in latency to and duration of SWDs and seizures between lithium-saline and lithium-pilocarpine exposed rats. Thus, SE induced by lithium and pilocarpine early in life does not change the sensitivity to limbic seizures or seizures induced by GABA(A) antagonists during adulthood.
Asunto(s)
Estado Epiléptico/fisiopatología , Envejecimiento , Animales , Animales Recién Nacidos , Corteza Cerebelosa/fisiopatología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Femenino , Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-A , Ácido Kaínico/farmacología , Litio , Masculino , Agonistas Muscarínicos , Pentilenotetrazol/farmacología , Picrotoxina/farmacología , Pilocarpina , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción , Estado Epiléptico/inducido químicamenteRESUMEN
Lithium-pilocarpine, a relevant model of temporal lobe epilepsy was used to test the neuroprotective and antiepileptogenic effects of carisbamate. Status epilepticus (SE) was induced in adult rats by lithium and pilocarpine. Carisbamate (30, 60, 90, and 120 mg/kg) was injected at 1 and 9 h after SE onset and continued twice daily for 6 additional days. The reference groups received diazepam instead of carisbamate. Neuroprotection was assessed during the first 24 h of SE with Fluoro-Jade B and after 14 days with thionine staining. SE severity and epileptic outcome were assessed by video, and surface and depth electroencephalographic recordings. At the two highest doses, carisbamate treatment reduced SE severity; produced strong neuroprotection of hippocampus, ventral cortices, thalamus, and amygdala; prevented mossy fiber sprouting in the dentate gyrus of the hippocampus; and delayed or suppressed the occurrence of spontaneous motor seizures. Rats with no spontaneous motor seizures displayed spike-and-wave discharges that share all the characteristics of absence seizures. In conclusion, carisbamate is able to induce strong neuroprotection and affect the nature of epileptogenic events occurring during and after lithium-pilocarpine status epilepticus, reflecting marked insult- and disease-modifying effects.
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Carbamatos/uso terapéutico , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Cloruro de Litio/toxicidad , Pilocarpina/toxicidad , Animales , Epilepsia del Lóbulo Temporal/fisiopatología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Thresholds to pentylenetetrazol (PTZ) seizures were usually based only on clinical symptoms. Our purpose was to use electroclinical patterns to assess the efficacy of a ketogenic and/or calorie-restricted diet on PTZ-induced seizures. METHODS: Forty 50-day-old rats were divided in four weight-matched groups and fed controlled diets: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), and hypocalorie ketogenic (HK). After 21 days, blood glucose and beta-hydroxybutyrate levels were determined and seizures were induced by continuous infusion of PTZ. The clinical and EEG thresholds to each seizure pattern were compared between the different groups. RESULTS: The electroclinical course of PTZ-induced seizures was similar in all groups. The HK group exhibited higher thresholds than the other ones for most clinical features: absence (p = 0.003), first overt myoclonia (p = 0.028), clonic seizure (p = 0.006), and for EEG features: first spike (p = 0.036), first spike-and-wave discharge (p = 0.014), subcontinuous spike-and-wave discharges (p = 0.005). NK, HC, and NC groups were not significantly different from each other. Blood glucose and beta-hydroxybutyrate levels were not correlated with electroclinical seizure thresholds. After the clonic seizure, despite stopping PTZ infusion, a tonic seizure occurred in some animals, without significant difference regarding the diet. CONCLUSION: This approach permitted a precise study of the electroclinical course of PTZ-induced seizures. In addition to the usually studied first overt myoclonia, we clearly demonstrated the efficiency of a calorie restricted KD in elevating thresholds to most electroclinical seizure patterns. We confirmed the lack of efficiency of the KD to reduce seizure severity once the seizure has started.
Asunto(s)
Restricción Calórica/métodos , Electroencefalografía/estadística & datos numéricos , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Cetosis/metabolismo , Pentilenotetrazol , Ácido 3-Hidroxibutírico/sangre , Animales , Glucemia/análisis , Peso Corporal/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/metabolismo , Modelos Animales de Enfermedad , Ingestión de Energía , Epilepsia/dietoterapia , Cetosis/etiología , Masculino , Ratas , Ratas WistarRESUMEN
PURPOSE: Measurement of local cerebral blood flow (LCBF) is routinely used to locate the areas involved in generation and spread of seizures in epilepsy patients. Because the spatial distribution and extent of ictal CBF depends on the epileptogenic network, but also on the timing of injection of tracer, we used a rat model of amygdala-kindled seizures to follow the time-dependent changes in the distribution of LCBF changes. METHODS: Rats were implanted in the left amygdala and were fully kindled. LCBF was measured by the quantitative [(14)C]iodoantipyrine autoradiographic technique bilaterally in 35 regions. The tracer was injected at 30 s before seizure induction (early ictal), simultaneous with the application of stimulation (ictal), at 60 s after stimulation (late ictal), at the end of the electrical afterdischarge (early postictal), and at 6 min after the stimulation (late postictal). RESULTS: Rates of LCBF increased over control levels during the early ictal phase ipsilaterally in medial amygdala, frontal cortex, and ventromedian thalamus and bilaterally in the whole hippocampus, thalamic nuclei, and basal ganglia. During the ictal phase, all regions underwent hyperperfusion (81-416% increases). By 60 s after stimulation, rates of LCBF returned to control levels in most brain areas, despite ongoing seizure activity. At later times, localized foci of hypoperfusion were observed in hippocampus bilaterally, with a slight predominance in CA1 on the side of origin of the seizures. CONCLUSION: This study shows a rapid spread of activation from the stimulated amygdala bilaterally to numerous limbic, cortical, and subcortical structures. The largest hyperperfusion was recorded during the ictal period with tracer injections simultaneous with the stimulation. The unilateral site of origin of seizures led to minor asymmetrical and lateralized findings, merely at early ictal and late postictal times, whereas intermediate tracer injections induced bilateral changes. Only late postictal measurements allowed the identification of significant changes in focal structures: the hippocampus is known to play a critical role in the spread of limbic seizures.