RESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra and appearance of protein aggregates (Lewy bodies) consisting predominantly of α-synuclein in neurons. PD is currently recognized as a multisystem disorder characterized by severe motor impairments and various non-motor symptoms. Cognitive decline is one of the most common and worrisome non-motor symptoms. Moderate cognitive impairments (CI) are diagnosed already at the early stages of PD, usually transform into dementia. The main types of CI in PD include executive dysfunction, attention and memory decline, visuospatial impairments, and verbal deficits. According to the published data, the following mechanisms play an essential role demonstrates a crucial importance in the decline of the motor and cognitive functions in PD: (1) changes in the conformational structure of transsynaptic proteins and protein aggregation in presynapses; (2) synaptic transmission impairment; (3) neuroinflammation (pathological activation of the neuroglia); (4) mitochondrial dysfunction and oxidative stress; (5) metabolic disorders (hypometabolism of glucose, dysfunction of glycolipid metabolism; and (6) functional rearrangement of neuronal networks. These changes can lead to the death of dopaminergic cells in the substantia nigra and affect the functioning of other neurotransmitter systems, thus disturbing neuronal networks involved in the transmission of information related to the regulation of motor activity and cognitive functions. Identification of factors causing detrimental changes in PD and methods for their elimination will help in the development of new approaches to the therapy of PD. The goal of this review was to analyze pathological processes that take place in the brain and underlie the onset of cognitive disorders in PD, as well as to describe the impairments of cognitive functions in this disease.
Asunto(s)
Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Disfunción Cognitiva/etiología , Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Redes Neurales de la ComputaciónRESUMEN
Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca2+ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed.
Asunto(s)
Neurotoxinas , Enfermedad de Parkinson , Animales , Ratas , Oxidopamina , Uridina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Encéfalo , Adenosina TrifosfatoRESUMEN
The dentate gyrus (DG) is part of the hippocampal formation and is essential for important cognitive processes such as navigation and memory. The oscillatory activity of the DG network is believed to play a critical role in cognition. DG circuits generate theta, beta, and gamma rhythms, which participate in the specific information processing performed by DG neurons. In the temporal lobe epilepsy (TLE), cognitive abilities are impaired, which may be due to drastic alterations in the DG structure and network activity during epileptogenesis. The theta rhythm and theta coherence are especially vulnerable in dentate circuits; disturbances in DG theta oscillations and their coherence may be responsible for general cognitive impairments observed during epileptogenesis. Some researchers suggested that the vulnerability of DG mossy cells is a key factor in the genesis of TLE, but others did not support this hypothesis. The aim of the review is not only to present the current state of the art in this field of research but to help pave the way for future investigations by highlighting the gaps in our knowledge to completely appreciate the role of DG rhythms in brain functions. Disturbances in oscillatory activity of the DG during TLE development may be a diagnostic marker in the treatment of this disease.
Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Giro Dentado/fisiología , Ritmo Gamma , Hipocampo/fisiología , Neuronas/fisiologíaRESUMEN
Cortical oscillations in different frequency bands have been shown to be intimately involved in exploration of environment and cognition. Here, the local field potentials in the hippocampus, the medial prefrontal cortex (mPFC), and the medial entorhinal cortex (mEC) were recorded simultaneously in rats during the execution of the episodic-like memory task. The power of theta (~4-10 Hz), slow gamma (~25-50 Hz), and fast gamma oscillations (~55-100 Hz) was analyzed in all structures examined. Particular attention was paid to the theta coherence between three mentioned structures. The modulation of the power of gamma rhythms by the phase of theta cycle during the execution of the episodic-like memory test by rats was also closely studied. Healthy rats and rats one month after kainate-induced status epilepticus (SE) were examined. Paroxysmal activity in the hippocampus (high amplitude interictal spikes), excessive excitability of animals, and the death of hippocampal and dentate granular cells in rats with kainate-evoked SE were observed, which indicated the development of seizure focus in the hippocampus (epileptogenesis). One month after SE, the rats exhibited a specific impairment of episodic memory for the what-where-when triad: unlike healthy rats, epileptogenic SE animals did not identify the objects during the test. This impairment was associated with the changes in the characteristics of theta and gamma rhythms and specific violation of theta coherence and theta/gamma coupling in these structures in comparison with the healthy animals. We believe that these disturbances in the cortical areas play a role in episodic memory dysfunction in kainate-treated animals. These findings can shed light on the mechanisms of cognitive deficit during epileptogenesis.
Asunto(s)
Neocórtex , Estado Epiléptico , Animales , Ritmo Gamma , Hipocampo/fisiología , Ácido Kaínico/toxicidad , Ratas , Ritmo Teta/fisiologíaRESUMEN
The hippocampal theta rhythm (4-12 Hz) is one of the most important electrophysiological processes in the hippocampus, it participates in cognitive hippocampal functions, such as navigation in space, novelty detection, and declarative memory. We use neural network modeling to study the mechanism of theta rhythm emergence in the CA1 microcircuitry. Our model of the CA1 field includes biophysical representation of major cell types related to the theta rhythm emergence: excitatory pyramidal cells and two types of inhibitory interneurons, PV+ basket cells and oriens lacunosum-moleculare (OLM) cells. The main inputs to the CA1 cells come from the entorhinal cortex via perforant pathway, the CA3 field via Schaffer collaterals, and the medial septum via fimbria-fornix. By computer simulations we investigated the influence of each input, intrinsic parameters of neurons, and connections between neurons on phase coupling between the theta rhythm and the firing of pyramidal, PV+ basket and OLM cells in the CA1. We found that the input from the CA3 field via Schaffercollaterals plays a major role in the formation of phase relations that have been observed in experiments in vivo. The direct input from the medial septum participates in the formation of proper phase relations, but it is not crucial for the production of the theta rhythm in CA1 neural populations.
Asunto(s)
Región CA1 Hipocampal/fisiología , Redes Neurales de la Computación , Células Piramidales/fisiología , Ritmo Teta/fisiología , Animales , Región CA1 Hipocampal/citología , Corteza Entorrinal/fisiología , Hipocampo/citología , Hipocampo/fisiología , Interneuronas/fisiología , Neuronas/fisiologíaRESUMEN
Alzheimer's disease (AD) and temporal lobe epilepsy (TLE) are the most common forms of neurodegenerative disorders characterized by the loss of cells and progressive irreversible alteration of cognitive functions, such as attention and memory. AD may be an important cause of epilepsy in the elderly. Early diagnosis of diseases is very important for their successful treatment. Many efforts have been done for defining new biomarkers of these diseases. Significant advances have been made in the searching of some AD and TLE reliable biomarkers, including cerebrospinal fluid and plasma measurements and glucose positron emission tomography. However, there is a great need for the biomarkers that would reflect changes of brain activity within few milliseconds to obtain information about cognitive disturbances. Successful early detection of AD and TLE requires specific biomarkers capable of distinguishing individuals with the progressing disease from ones with other pathologies that affect cognition. In this article, we review recent evidence suggesting that magnetoencephalographic recordings and coherent analysis coupled with behavioral evaluation can be a promising approach to an early detection of AD and TLE. Highlights -Data reviewed include the results of clinical and experimental studies.-Theta and gamma rhythms are disturbed in epilepsy and AD.-Common and different behavioral and oscillatory features of pathologies are compared.-Coherent analysis can be useful for an early diagnostics of diseases.
RESUMEN
OBJECTIVE: Status epilepticus (SE) provokes changes, which lead to neuronal alterations. Endocannabinoids (eCBs) can affect the neuronal survival during excitotoxicity and brain damage. Using a kainic acid (KA)-induced experimental SE model, we investigated whether cellular changes entail damage to endoplasmic reticulum (ER), mitochondria, and nuclei in hippocampal cells (CA1 field), and whether these alterations can be diminished by treatment with URB597, an inhibitor of eCB enzymatic degradation. MATERIAL AND METHODS: SE was induced in Wistar rats by the microinjection of KA into the lateral ventricle. URB597 or a vehicle (10% DMSO) were injected in the same way into the brain of animals 24h after the KA infusion and then daily for the next nine days. The behavior of animals was controlled visually and recorded with a video system. The intensity of SE significantly varied in different animals. Convulsive (stages 3-5 according to the Racine scale) and nonconvulsive seizures (mainly stages 1, 2 and rarely 3, 4) were recognized. RESULTS: Two weeks after SE, a significant loss of hippocampal cells occurred in animals with KA injections. In survived cells, ultrastructural alterations in ER, mitochondria, and nuclei of hippocampal neurons were observed. The degree of cell injury depended on the severity of SE. Alterations evoked by moderate seizures were prevented or diminished by URB597, but strong seizures induced mostly irreversible damage. CONCLUSIONS: The beneficial impact of the FAAH inhibitor URB597 can give impetus to the development of novel neuroprotective strategies.
Asunto(s)
Benzamidas/farmacología , Carbamatos/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estado Epiléptico/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Animales , Muerte Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/patología , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/patología , Inhibidores Enzimáticos/farmacología , Hipocampo/patología , Ácido Kaínico , Microscopía Electrónica , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Neuronas/patología , Ratas Wistar , Índice de Severidad de la Enfermedad , Estado Epiléptico/patologíaRESUMEN
Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. The cannabinoid CB1 receptor antagonist AM251 was also tested. Coadministration of AM404 or URB597 with KA reduced acute behavioral seizures, but electrographic seizures were still registered. During the three months following KA injection, various trends in the oscillatory activities were observed, including an increase in activity power at all frequency bands in the hippocampus and a progressive long-term decrease in the medial septum. In the KA- and KA/AM251-treated animals, disturbances of the oscillatory activities were accompanied by cell loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. Injections of AM404 or URB597 softened alterations in electrical activity of the brain and prevented hippocampal neuron loss and synaptic reorganization. Our results demonstrate the protective potential of the eCB system during excitotoxic influences.
Asunto(s)
Endocannabinoides/farmacología , Endocannabinoides/uso terapéutico , Receptor Cannabinoide CB1/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/metabolismo , Giro Dentado/metabolismo , Cobayas , Hipocampo/efectos de los fármacos , Ácido Kaínico/efectos adversos , Ácido Kaínico/farmacología , Neuronas/metabolismo , Piperidinas , Pirazoles , Receptor Cannabinoide CB1/antagonistas & inhibidores , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamenteRESUMEN
It is widely believed that the theta rhythm in the hippocampus is caused by the rhythmic input from the medial septum-diagonal band of Broca (MSDB). The main MSDB output is formed by GABAergic projection neurons which are divided into two subpopulations and fire at different phases of the hippocampal theta rhythm. The MSDB also contains projection cholinergic, glutamatergic, and non-projection GABAergic neurons. These cell populations innervate each other and also GABAergic projection neurons and participate in the formation of the synchronous rhythmic output to the hippocampus. The purpose of this study is to work out a model of interactions between all neural populations of the MSDB that underlie the formation of the synchronous septal theta signal. The model is built from biologically plausible neurons of the Hodgkin-Huxley type and its architecture reflects modern data on the morphology of neural connections in the MSDB. The model satisfies the following requirements: (1) a large portion of neurons is fast-spiking; (2) the subpopulations of GABAergic projection neurons contain endogenous pacemaker neurons; (3) the phase shift of activity between subpopulations of GABAergic projection neurons is equal to about 150°; and (4) the strengths of bidirectional connections between the subpopulations of GABAergic projection cells are different. It is shown that the theta rhythm generation can be performed by a system of glutamatergic and GABAergic non-projection neurons. We also show that bursting pacemaker neurons in the subpopulation of projection GABAergic neurons play a significant role in the formation of stable antiphase outputs from the MSDB to the hippocampus.
Asunto(s)
Comunicación Celular/fisiología , Modelos Neurológicos , Neuronas/fisiología , Núcleos Septales/citología , Núcleos Septales/fisiología , Ritmo Teta/fisiología , Potenciales de Acción , Proteínas Adaptadoras del Transporte Vesicular , Animales , Simulación por Computador , Humanos , Red Nerviosa , Proteínas del Tejido Nervioso , Neuronas/clasificaciónRESUMEN
Status epilepticus (SE) is a medical emergency associated with a high rate of mortality if not treated promptly. Exogenous and endogenous cannabinoids have been shown to possess anticonvulsant properties both in vivo and in vitro. Here we study the influence of endocannabinoid metabolism on the development of kainic acid-induced SE in guinea pigs. For this purpose, the inhibitors of endocannabinoid transport, AM404, and enzymatic (fatty acid amide hydrolase) degradation, URB597, were applied. Cannabinoid CB1 receptor antagonist, AM251, was also tested. Animal behavior as well as local electric field potentials in four structures: medial septum, hippocampus, entorhinal cortex and amygdala were analyzed when AM404 (120nmol), URB597 (4.8nmol) or AM251 (20nmol) were administrated alone or together with 0.4µg of kainic acid. All substances were injected i.c.v. AM404, URB597 or AM251 administered alone did not alter markedly local field potentials of all four studied structures in the long-term compared with their basal activity. AM404 and URB597 significantly alleviated kainic acid-induced SE, decreasing behavioral manifestations, duration of seizure events and SE in general without changing the amplitude of local field potentials. AM251 did not produce distinct effects on SE in terms of our experimental paradigm. There was no apparent change of the seizure initiation pattern when kainic acid was coadministrated with AM404, URB597 or AM251. The present study provides electrophysiologic and behavioral evidences that inhibition of endocannabinoid metabolism plays a protective role against kainic acid-induced SE and may be employed for therapeutic purposes. Further investigations of the influences of cannabinoid-related compounds on SE genesis and especially epileptogenesis are required.
Asunto(s)
Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Endocannabinoides/metabolismo , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/fisiopatología , Amidohidrolasas/metabolismo , Animales , Ácidos Araquidónicos/farmacología , Benzamidas/farmacología , Transporte Biológico/efectos de los fármacos , Antagonistas de Receptores de Cannabinoides/farmacología , Carbamatos/farmacología , Cobayas , Ácido Kaínico , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatologíaRESUMEN
Although the presence and importance of oscillations in cortical structures is well-documented, little is known about this rhythmic activity in subcortical areas. In waking guinea pigs, during their inattentive rest, local field potentials (LFPs) were recorded simultaneously in eight brain structures. In the cortical areas (prefrontal and entorhinal fields, hippocampus, dentate gyrus) and subcortical ones (medial and lateral septal nuclei, central nucleus of amygdala, and supramammillary nucleus), different types of oscillations were observed: delta (0.5-4Hz), theta (4-8), alpha (10-12), gamma (40-80), and high-frequency, presumable ripples (100-200Hz). In all structures, low-frequency oscillations (delta and theta) were more powerful than high-frequency ones. Structural communications in different bands of rhythmic activity were expressed differently. On the whole they were the more intensive, the stronger were the oscillations, however, this was not the absolute rule. A long-term (about a month) daily injection of l-glutamate into the medial septal region induced significant changes in theta, gamma, and high-frequency oscillations in most regions examined. The correlations of some structures also changed; they significantly decreased between the entorhinal cortex and hippocampus in the theta band and between the medial septum and central amygdala in the gamma band. During permanent septal glutamate infusion, distinct signs of epileptogenesis were revealed (epileptiform activity, seizure behavior of animals, and formation of aberrant fibers in the hippocampus). Thus, we believe that the glutamatergic system of medial septum can participate in the development of epilepsy. The earliest sign of pathology in electrical activity was alterations in high-frequency oscillations in the dentate gyrus and medial septum, but the strongest changes were in theta and especially gamma rhythms in many structures. The data obtained help to advance our understanding of the basic mechanisms of brain functioning and its disturbances in seizure pathology.
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Ondas Encefálicas/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Ácido Glutámico/toxicidad , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Animales , Encéfalo/patología , Ondas Encefálicas/fisiología , Electrodos Implantados , Epilepsia/inducido químicamente , Epilepsia/patología , Epilepsia/fisiopatología , Femenino , Cobayas , Masculino , Convulsiones/patologíaRESUMEN
Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. It is well-documented that intrinsic neuronal oscillations and provided by them communications between brain structures are of importance for cognition. Epilepsy disturbs these brain rhythms and presumably therefore affects memory. Here we review studies on cellular and systemic levels devoted to the TLE-induced disturbance of theta oscillations in the septohippocampal system. Special attention is paid to the role of damage of septal and hippocampal GABAergic cells in theta activity abnormalities. We also compare differences between native (in vivo) theta oscillations with those obtained in in vitro preparations of hippocampus and medial septum and find that in vitro they resemble epileptiform activity in some respects.
Asunto(s)
Epilepsia del Lóbulo Temporal/patología , Hipocampo/fisiopatología , Vías Nerviosas/fisiología , Tabique del Cerebro/fisiopatología , Ritmo Teta/fisiología , Animales , HumanosRESUMEN
The supposition was advanced that the neuronal theta rhythmicity is the key mode of signal selection at the hippocampal level. To address this hypothesis, the experimental data on the responses of putative hippocampal interneurons of the stratum oriens CA1-CA3 to stimulation during enhanced theta rhythm and after its blockade are reviewed. Both a strong increase and a decrease of the natural theta rhythm disturbed the reactions of hippocampal neurons; during theta augmentation, the responses were masked or disappeared, and after theta blockade, they lost the ability to habituate. In both cases, two important events were broken: the resetting of the background activity and the phase-locking of theta cycles to stimulus. These data allow one to suppose that only important stimuli are normally capable to evoke these events and these stimuli are selected for recording. When the response to a significant stimulus occurs, the following theta prevents the responses to other stimuli. This probably protects the hippocampal activity from interference from irrelevant signals. Presumably, the absence of the theta deprives the hippocampus of this protection. During enhanced and persistent theta oscillations, the reset disappeared and theta bursts were generated without stimulus locking. In this state, the system is probably closed and the information cannot be recorded. During the theta blockade, the reset was too long and did not habituate. In this case, the system is open for any signals and the hippocampus loses the ability to select signal. This analysis suggests that information selection in the hippocampus may be performed with the participation of nonpyramidal neurons.
Asunto(s)
Hipocampo/fisiología , Neuronas/fisiología , Animales , Hipocampo/citología , HumanosRESUMEN
The multiunit activity in the medial septal-diagonal band complex (MSDB) and field potentials of the hippocampus were simultaneously recorded in waking healthy rabbits (control) and in the same animals that were then exposed to kindling stimulation of the perforant path. In the control, the bursts of spikes in one group of rhythmic MSDB neurons phase-locked to the top of theta waves in the hippocampus, and in the second group, to the trough of these waves. The stimulation evoked seizure afterdischarges in the hippocampus and seizure bursts of spikes separated by periods of inhibition in MSDB neurons. In the first group of septal cells, seizure bursts coincided with inhibitory periods between afterdischarges in the hippocampus; in the second group, these bursts were observed during seizure afterdischarges, suggesting that different MSDB cells play opposite roles in the development of seizures. Evoked afterdischarges were spontaneously followed by recurrent ictal events; neuronal oscillations at the theta (6-7 Hz) or "twice-theta" frequency (12-14 Hz) preceded these secondary epileptic discharges. As a result of kindling, interictal spikes were recorded in the hippocampus; at the same time, synchronous bursts of many cells appeared in the MSDB. In the epileptic brain, the frequency of both the hippocampal theta rhythm and MSDB neuronal theta bursts increased; in the septum, an augmentation of neuronal rhythmicity was also observed. Theta oscillations, either spontaneous or evoked by sensory stimulation, abolished the epileptiform events. Evidently, the activities within the theta range during preictal and interictal periods are of different significance in the generation of seizures.
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Epilepsia/patología , Epilepsia/fisiopatología , Potenciales Evocados/fisiología , Neuronas/fisiología , Tabique del Cerebro/patología , Ritmo Teta , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica/efectos adversos , Cobayas , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Análisis Numérico Asistido por Computador , Vía Perforante/fisiopatología , Periodicidad , Conejos , Tabique del Cerebro/fisiopatologíaRESUMEN
Field potentials of the hippocampus and the medial septal-diagonal band complex (MSDB) were recorded in the control and during the kindling stimulation of the perforant path in waking guinea pigs. Changes in the correlation of activities of these structures during stimulation-evoked seizures (model of acute epilepsy) and during epileptogenesis elicited by the kindling (model of chronic epilepsy) were analysed. In the control, a high correlation between the background activities of the hippocampus and MSDB was observed. In the first days of stimulation at the parameters that evoked seizure discharges in the hippocampus, the MSDB did not show the epileptiform activity; however, repeated daily stimulation gave rise to epileptiform discharges, which increased with time. As a result of kindling, the MSDB became capable of generating seizure activity irrespective of the hippocampus. The degree of correlation between the activities of the two structures sharply decreased during "acute" and "chronic" seizures. In the process of kindling, a progressive disintegration of activities of the hippocampus and MSDB was revealed, indicating the disturbance of the functioning of septohippocampal network during epileptogenesis. The data obtained add to the knowledge about the mechanisms of temporal lobe epilepsy and may help to develop new approaches to the therapy of this disease.
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Banda Diagonal de Broca/fisiopatología , Electroencefalografía , Epilepsia/fisiopatología , Hipocampo/fisiopatología , Excitación Neurológica/fisiología , Animales , Cobayas , Vía Perforante/fisiopatología , Convulsiones/fisiopatologíaRESUMEN
Changes in the activity of putative interneurons of the stratum oriens of the hippocampus and hippocampal EEG after the delivery of the GABAA receptor antagonist bicuculline (1.0nmol/1microl) to the medial septal region were investigated in awake rabbits. The injection of bicuculline produced a sharp increase in the firing rate in 94.3% of hippocampal cells. The effect of bicuculline on the neuronal theta rhythmicity depended on the number of injections. The first five daily infusions decreased the theta activity in 85.7% of cells. On the fourth to fifth experimental days paroxysmal discharges and 8-15Hz oscillations were recorded in the hippocampal EEG. Six to seven further daily bicuculline injections following a brief diminution of theta activity produced a sharp augmentation of theta oscillations in 78.9% of cells and provoked seizures. Immediately before seizures, stabilization of theta bursts and an increase in burst frequency was usually observed in putative interneurons. During seizures, neuronal rhythmic activity was either disordered and then turned into seizure discharges or was inhibited, partially or completely. In the hippocampal EEG, the power of theta rhythm before seizures usually strongly increased compared with controls. Injection of the GABAA agonist muscimol (30nmol/1microl) 15min before bicuculline infusion prevented the development of seizures. These findings suggest that the interplay between septal neurons via GABAA receptors is critical in the tuning of septal output signals that insure generation of natural theta rhythm as well as adequate functioning of the hippocampus.