RESUMEN
Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3 h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss.
Asunto(s)
Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Vestíbulo del Laberinto/fisiopatología , Animales , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Neuronas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Neural cell adhesion molecule (NCAM) is frequently associated with polysialic acid (PSA), and its function is highly dependent on this polysialylation. PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. STX and PST are the enzymes responsible for NCAM polysialylation. We investigated whether unilateral long-term potentiation (LTP) induction in vivo, in adult rat dentate gyrus (DG), triggered NCAM polysialylation by STX and PST produced in the hippocampus. We found that levels of STX and PST mRNA increased strongly since the early stage of hippocampal LTP and remained high during the maintenance of DG-LTP for 4 h. This rapid increase in polysialyltransferase gene expression occurred in both the hippocampi, probably resulting from bilateral LTP induction by strong unilateral HFS. Thus, LTP triggers interhemispheric molecular changes in the hippocampal network. This study is the first to describe the effects of LTP induction and maintenance on polysialyl-transferases in vivo. Our findings suggest that hippocampal synaptic remodeling requires NCAM polysialylation.
Asunto(s)
Giro Dentado/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Potenciación a Largo Plazo/genética , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Sialiltransferasas/genética , Animales , Expresión Génica , Perfilación de la Expresión Génica , Masculino , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sialiltransferasas/biosíntesisRESUMEN
The prevalent theory in learning and memory processes is that they are underlain by short and long-term changes in synaptic weight, which continuously modulates neural networks during acquisition and recall. This synaptic plasticity has been revealed by recording extracellular field potentials. The enhancement of synaptic transmission was primarily noted in the hippocampus and was named long-term potentiation (LTP). The opposite mechanism, long-term depression (LTD), a reduction of synaptic transmission, was first discovered in the cerebellum. Since then, the LTP-model has been studied mainly using in vitro and acute anesthetized in vivo preparations. This approach has led to remarkable progress in the comprehension of intracellular molecular processes during LTP and LTD. In this review, we focus mainly on what we can learn about molecular events using extracellular field potential recordings with a more ecological model, i.e., studies using the freely behaving animal, with animals that are genetically modified or not, in several behavioral paradigms aimed at gaining insight into some of the conflicting results obtained with in vitro and in vivo preparations.
Asunto(s)
Potenciales de Acción/fisiología , Conducta Animal/fisiología , Neuronas/fisiología , Neurociencias , Integración de Sistemas , Animales , Modelos Neurológicos , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Roedores/fisiologíaRESUMEN
We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras/metabolismo , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Proteínas de Anclaje a la Quinasa A , Animales , Anticonvulsivantes/farmacología , Estimulación Eléctrica , Electrochoque , Hibridación in Situ , Masculino , Plasticidad Neuronal/fisiología , Piperazinas/farmacología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/metabolismo , Regulación hacia ArribaRESUMEN
This article begins with a review of recent experiments investigating the synaptic efficacy changes occurring in rat dentate gyrus and piriform cortex during an associative olfactory task. In all these experiments, animals were trained to discriminate among an artificial cue, a patterned electrical stimulation distributed to the lateral olfactory tract associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral olfactory tract were recorded in the ipsilateral piriform cortex before and just after each training session. Monosynaptic field and polysynaptic field potentials evoked by single electrical stimuli applied respectively to the lateral perforant pathway and lateral olfactory tract were also recorded in ipsilateral dentate gyrus. The results showed an increase in synaptic efficacy subsequent to the first training session in the dentate gyrus network when compared with piriform cortex at the later stage of the learning. The early increase of monosynaptic response in the dentate gyrus was observed immediately after the first learning session but disappeared 24 h later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of the last (fifth) session. The polysynaptic potential recorded in this structure increased substantially when rats began to discriminate the leaming cues, usually after the second or third learning session. Then, from the third to the fifth session, an LTP like-phenomenon appeared in piriform cortex when rats perfectly mastered the associations. Experiments using high-frequency stimulation to prevent changes in gyrus dentatus indicated that the onset of the observed depression was necessary for the learning of the olfactory associations. The fact that hippocampal and cortical neuronal networks exhibited different timing in synaptic efficacy changes could physiologically explain learning and memory processes.
Asunto(s)
Giro Dentado/fisiología , Aprendizaje/fisiología , Sistema Límbico/fisiología , Memoria/fisiología , Sinapsis/fisiología , Animales , Condicionamiento Operante/fisiología , Señales (Psicología) , Estimulación Eléctrica , Potenciales Evocados/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Potenciación a Largo Plazo/fisiología , Ratas , Recompensa , Factores de TiempoRESUMEN
Modifications of synaptic efficacy in the dentate gyrus were investigated during an olfactory associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue, associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral perforant path were recorded in the granular layer of the ipsilateral dentate gyrus prior to and just after each training session. An early increase in this response was observed just after the first learning session but disappeared 24 hours later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of a last (fifth) session. When a group of naive animals was pseudo-conditioned, no increase was observed and the synaptic depression was noted since the onset of the second session. In a group of rats similarly trained for only one session, and in which EPSPs were recorded throughout the 24 hours that followed, it was demonstrated that the increase lasted at least two hours, while the significant synaptic depression started after the fourth hour. These results are consistent with the early involvement of the dentate gyrus in learning the association between the cues and their respective rewards. These early integrative processes physiologically observed in dentate gyrus suggest early hippocampal processing before dentate gyrus reactivation via entorhinal cortex which will allow long-term memory storage in cortical areas once the meaning of the olfactory cues is learned.
Asunto(s)
Aprendizaje por Asociación/fisiología , Giro Dentado/fisiología , Vías Olfatorias/fisiología , Animales , Señales (Psicología) , Aprendizaje Discriminativo/fisiología , Estimulación Eléctrica/métodos , Potenciales Evocados , Potenciales Postsinápticos Excitadores , Masculino , Odorantes , Vía Perforante/fisiología , Estimulación Luminosa , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
It is not known whether NMDA receptor-dependent long-term potentiation (LTP) is mediated by similar molecular mechanisms in different hippocampal areas. To address this question we have investigated changes in immediate early gene and protein expression in two hippocampal subfields following the induction of LTP in vivo and in vitro. In granule cells of the dentate gyrus, LTP induced in vivo by tetanic stimulation of the perforant path was followed by strong induction of the immediate early genes (IEGs) Zif268, Arc and Homer. The increase in Zif268 mRNA was accompanied by an increase in protein expression. In contrast, we were unable to detect modulation of the IEGs Zif268, Arc, Homer and HB-GAM following induction of LTP by high-frequency stimulation of the commissural projection to CA1 pyramidal cells in vivo. In this pathway, we also failed to detect modulation of Zif268 protein levels. Zif268, Arc and Homer can be modulated in CA1 pyramidal cells approximately twofold after electroshock-induced maximal seizure, which demonstrates potential responsiveness to electrical stimuli. When LTP was induced in vitro neither CA1 pyramidal cells nor granule cells showed an increase in Zif268, Arc or Homer mRNA. However, in the slice preparation, granule cells have a different transcriptional state as basal IEG levels are elevated. These results establish the existence of subfield-specific transcriptional responses to LTP-inducing stimulation in the hippocampus of the intact animal, and demonstrate that in area CA1-enhanced transcription of Zif268, Arc and Homer is not required for the induction of late LTP.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Genes Inmediatos-Precoces/fisiología , Hipocampo/metabolismo , Proteínas Inmediatas-Precoces , Potenciación a Largo Plazo/fisiología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Giro Dentado/citología , Giro Dentado/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz , Electrochoque/efectos adversos , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/citología , Proteínas de Andamiaje Homer , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuropéptidos/genética , Neuropéptidos/metabolismo , Técnicas de Cultivo de Órganos , Vía Perforante/citología , Vía Perforante/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células Piramidales/citología , Células Piramidales/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsis/metabolismo , Sinapsis/ultraestructura , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In this report, we investigated the electrophysiological dynamics of the neuronal circuit including the dentate gyrus during an associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue associated with a water reward, and a natural odor associated with a light flash. Polysynaptic field potential responses, evoked by a single electrical stimulation of the same lateral olfactory tract electrode, were recorded in the molecular layer of the ipsilateral dentate gyrus prior to and just after each training session. An increase in this response was observed when a significant discrimination of the two cues began. A positive correlation was found between the change in the polysynaptic potentiation and behavioral performances. The onset latency of the potentiated polysynaptic response was 35-45 ms. When a group of naive animals was pseudoconditioned, no change in field potential was observed. These results are consistent with the hypothesized dynamic activation of the dentate gyrus early in the making of association, allowing gradual storage of associative information in a defined set of synapses. Moreover, the onset latency of the potentiated response suggests the existence of reactivating hippocampal loops during the processing of associative information.
Asunto(s)
Aprendizaje por Asociación/fisiología , Giro Dentado/fisiología , Aprendizaje Discriminativo/fisiología , Potenciación a Largo Plazo/fisiología , Análisis de Varianza , Animales , Estimulación Eléctrica , Masculino , Modelos Neurológicos , Odorantes , Vías Olfatorias/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción , Análisis de Regresión , Factores de TiempoRESUMEN
Within the past century it has been well established that most mature neurons lose their ability to divide. Since then, it has been assumed that behavioral performance leads to synaptic changes in the brain. The existence of these potential changes has been demonstrated in numerous experiments, and different mechanisms contributing to synaptic plasticity have been discovered. Many structures involved in different types of learning have now been identified. This article reviews the different methods used with mammals to detect electrophysiological modifications in synaptic plasticity following behavior. Evidence of long-term potentiation and long-term depression has been found in the hippocampus and cerebellum, respectively, and empirical data has been used to correlate these mechanisms with specific learning performance. Similar observations were made recently in the septum and amygdala. These phenomena seem to be involved in maintaining the performance in the cortical areas of the brain. Ongoing attempts to find the relationship between behavioral performance and modifications in synaptic efficacy allow to speculate upon the dynamics of cellular mechanisms that contribute to the ability of mammals to modify wide neuronal networks in the brain during their life.