RESUMEN
BACKGROUND: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aß42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.
Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Animales , Humanos , Memantina/uso terapéutico , RatasRESUMEN
Among aging-induced impairments, those affecting cognitive functions certainly represent one the most major challenge to face to improve elderly quality of life. In last decades, our knowledge on changes in the morphology and function of neuronal networks associated with normal and pathological brain aging has rapidly progressed, initiating the development of different pharmacological and behavioural strategies to alleviate cognitive aging. In particular, experimental evidences have accumulated indicating that the communication between neurons and its plasticity gradually weakens with aging. Because of its pivotal role for brain functional plasticity, the N-Methyld-Aspartate receptor subtype of glutamate receptors (NMDAr) has gathered much of the experimental interest. NMDAr activation is regulated by many mechanisms. Among is the mandatory binding of a co-agonist, such as the amino acid d-serine, in order to activate NMDAr. This mini-review presents the most recent information indicating how d-serine could contribute to mechanisms of physiological cognitive aging and also considers the divergent views relative of the role of the NMDAr co-agonist in Alzheimer's disease.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Cognición/fisiología , Expresión Génica , Glucosa/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Memoria/fisiología , Neuronas/metabolismo , Neuronas/patología , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
Age-related memory deficits have recently been associated with the impaired expression of D-serine-dependent synaptic plasticity in neuronal networks of the hippocampal CA1 area. However, whether such functional alterations are common to the entire hippocampus during aging remains unknown. Here, we found that D-serine was also required for the induction of N-methyl-D-aspartate receptor (NMDA-R)-dependent long-term potentiation (LTP) at perforant path-granule cell synapses of the dentate gyrus. LTP as well as isolated NMDA-R synaptic potentials were impaired in slices from aged rats, but in contrast to the CA1, this defect was not reversed by exogenous D-serine. The lower activation of the glycine-binding site by the endogenous co-agonist does not therefore appear to be a critical mechanism underlying age-related deficits in NMDA-R activation in the dentate gyrus. Instead, our data highlight the role of changes in presynaptic inputs as illustrated by the weaker responsiveness of afferent glutamatergic fibers, as well as changes in postsynaptic NMDA-R density. Thus, our study indicates that although NMDA-R-dependent mechanisms driving synaptic plasticity are quite similar between hippocampal circuits, they show regional differences in their susceptibility to aging, which could hamper the development of effective therapeutic strategies aimed at reducing cognitive aging.
Asunto(s)
Envejecimiento/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Memoria/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Envejecimiento/fisiología , Animales , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Fenómenos Electrofisiológicos , Femenino , Hipocampo/patología , Masculino , Trastornos de la Memoria/fisiopatología , Plasticidad Neuronal , Ratas , Ratas Sprague-DawleyRESUMEN
The learning and memory deficits associated with non-pathological ageing mainly result from alterations to the plasticity of neuronal network dynamics within the hippocampus. In addition to the broad spectrum of changes that affect the morphology and function of hippocampal excitatory circuits in the ageing brain, the impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDA-R) is a typical feature, altering the induction and maintenance of long-term potentiation, a major form of synaptic plasticity. In addition to glutamate, the binding of a co-agonist at the strychnine-insensitive glycine-binding site is required for NMDA-R activation. This review presents recent evidence that: (i) the amino acid D-serine is an endogenous co-agonist of synaptic NMDA-R and necessary for long-term potentiation expression, (ii) reduced d-serine levels in the hippocampus contribute to synaptic plasticity and memory deficits in normal ageing, and (iii) age-related oxidative stress selectively targets hippocampal serine racemase to impact D-serine availability in neuronal networks. These results emphasize the critical role of the hippocampal d-serine-dependent pathway in changes affecting neuronal network dynamics in physiological ageing that underlie memory deficits. In addition, the central role of serine racemase in these changes opens new perspectives in the search for relevant therapeutic strategies aimed at reducing age-related memory defects.
Asunto(s)
Envejecimiento/fisiología , Potenciación a Largo Plazo/fisiología , Trastornos de la Memoria/fisiopatología , Racemasas y Epimerasas/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Animales , Hipocampo/fisiología , Trastornos de la Memoria/enzimología , Ratones , Ratas , Sinapsis/fisiologíaRESUMEN
Unlike other serine proteases that are zymogens, the single-chain form of tissue plasminogen activator (sc-tPA) exhibits an intrinsic activity similar to that of its cleaved two-chain form (tc-tPA), especially in the presence of fibrin. In the central nervous system tPA controls brain functions and dysfunctions through its proteolytic activity. We demonstrated here, both in vitro and in vivo, that the intrinsic activity of sc-tPA selectively modulates N-methyl-D-aspartate receptor (NMDAR) signaling as compared with tc-tPA. Thus, sc-tPA enhances NMDAR-mediated calcium influx, Erk(½) activation and neurotoxicity in cultured cortical neurons, excitotoxicity in the striatum and NMDAR-dependent long-term potentiation in the hippocampal CA-1 network. As the first demonstration of a differential function for sc-tPA and tc-tPA, this finding opens a new area of investigations on tPA functions in the absence of its allosteric regulator, fibrin.
Asunto(s)
Neuronas/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacos , Activador de Tejido Plasminógeno/farmacología , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , N-Metilaspartato/toxicidad , Neuronas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/metabolismoRESUMEN
The rescue of cognitive function through environmental enrichment (EE) during aging has been extensively documented. However, the age at onset, the duration of EE, and the cerebral mechanisms required to obtain the greatest benefits still remain to be determined. We have recently shown that EE applied for 3 mo after the median lifespan, i.e., the age at which 50% of the population is still alive (from 17 to 20 mo in NMRI mice), failed to prevent cognitive deficits in senescent animals. In the present study, mice were exposed to EE prior to the median lifespan, and for a longer total duration (from 14 to 20 mo), before the assessment of memory performance and the electrophysiological properties of hippocampal neuronal networks. The EE prevented memory deficits and reduced anxiety as the animal aged. Moreover, EE attenuated the age-related impairment of basal glutamatergic neurotransmission in CA1 hippocampal slices, and reversed the decrease in isolated N-methyl-D-Aspartate receptor (NMDA-R)-dependent synaptic potentials. Surprisingly, EE did not prevent the age-related alteration of theta-burst-induced long-term potentiation (LTP). This study therefore suggests that EE needs to be initiated before the age corresponding to the median lifespan and/or required long duration (> 3 mo) to have an effect on cognitive aging. In addition, we show that EE probably acts through theta-burst-independent mechanisms of synaptic plasticity.
Asunto(s)
Envejecimiento/fisiología , Cognición/fisiología , Ambiente Controlado , Exposición a Riesgos Ambientales , Hipocampo/fisiología , Longevidad/fisiología , Envejecimiento/psicología , Animales , Ansiedad/prevención & control , Femenino , Trastornos de la Memoria/prevención & control , Ratones , Ratones Endogámicos , Plasticidad Neuronal/fisiología , Técnicas de Cultivo de Órganos , Sinapsis/fisiologíaRESUMEN
To gain insight into the contribution of d-serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d-serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are not found in the latter strain, which is therefore considered a model of healthy aging. Both mRNA and protein levels of serine racemase, the d-serine synthesizing enzyme, were decreased in the hippocampus but not in the cerebral cortex or cerebellum of aged Wistar rats, whereas the expression of d-amino acid oxidase, which degrades the amino acid, was not affected. Consequently, hippocampal levels of endogenous d-serine were significantly lower. In contrast, serine racemase expression and d-serine levels were not altered in the hippocampus of aged Lou/C/Jall rats. Ex vivo electrophysiological recordings in hippocampal slices showed a marked reduction in N-methyl-d-aspartate-receptor (NMDA-R)-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) in the CA1 area of aged Wistar rats, which were restored by exogenous d-serine. In contrast, NMDA-R activation, LTP induction and responses to d-serine were not altered in aged Lou/C/Jall rats. These results further strengthen the notion that the serine racemase-dependent pathway is a prime target of hippocampus-dependent cognitive deficits with aging. Understanding the processes that specifically affect serine racemase during aging could thus provide key insights into the treatment of memory deficits in the elderly.
Asunto(s)
Envejecimiento/fisiología , Hipocampo/fisiología , Trastornos de la Memoria/enzimología , Trastornos de la Memoria/fisiopatología , Racemasas y Epimerasas/antagonistas & inhibidores , Racemasas y Epimerasas/biosíntesis , Transducción de Señal , Envejecimiento/genética , Animales , Trastornos del Conocimiento/enzimología , Trastornos del Conocimiento/genética , Regulación Enzimológica de la Expresión Génica , Hipocampo/enzimología , Masculino , Trastornos de la Memoria/genética , Racemasas y Epimerasas/genética , Ratas , Ratas Wistar , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.
RESUMEN
Although memory impairments are a hallmark of aging, the degree of deficit varies across animal models, and is likely to reflect different states of deterioration in metabolic and endocrinological properties. This study investigated memory-related processes in young (3-4 months) and old (24 months) Sprague-Dawley rats (SD), which develop age-linked pathologies such as obesity or insulin-resistance and Lou/C/Jall rats, which do not develop such impairments. In short- and long-term memory recognition tasks, old Lou/C/Jall rats were never impaired whereas old SD rats were deficient at 1 and 24h latencies. The expression of N-methyl-d-aspartate receptors (NMDAR)-mediated synaptic plasticity in CA1 hippocampal networks shifted towards lower activity values in old Lou/C/Jall rats whereas long-term potentiation was impaired in age-matched SD rats. Age-related decrease in NR2A subunits occurred in both strains, extended to NR2B, NR1 and GluR1 subunits in older animals (28 months) but only in SD rats. Therefore, the Lou/C/Jall rats can be considered as a model of healthy aging, not only in terms of its preserved metabolism, but also in terms of cognition and synaptic plasticity.
Asunto(s)
Envejecimiento/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Envejecimiento/genética , Animales , Predisposición Genética a la Enfermedad , Hipocampo/fisiopatología , Resistencia a la Insulina/genética , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/fisiopatología , Memoria a Corto Plazo/fisiología , Obesidad/complicaciones , Obesidad/genética , Obesidad/metabolismo , Técnicas de Cultivo de Órganos , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Especificidad de la EspecieRESUMEN
Rather different from their initial image as passive supportive cells of the CNS, the astrocytes are now considered as active partners at synapses, able to release a set of gliotransmitter-like substances to modulate synaptic communication within neuronal networks. Whereas glutamate and ATP were first regarded as main determinants of gliotransmission, growing evidence indicates now that the amino acid D-serine is another important player in the neuronal-glial dialogue. Through the regulation of glutamatergic neurotransmission through both N-methyl-D-aspartate (NMDA-R) and non-NMDA-R, D-serine is helping in modelling the appropriate connections in the developing brain and influencing the functional plasticity within neuronal networks throughout lifespan. The understanding of D-serine signalling, which has increased linearly in the last few years, gives new insights into the critical role of impaired neuronal-glial communication in the diseased brain, and offers new opportunities for developing relevant strategies to treat cognitive deficits associated to brain disorders.
Asunto(s)
Encefalopatías/fisiopatología , Neuroglía/fisiología , Neuronas/fisiología , Serina/fisiología , Transducción de Señal , Envejecimiento , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Encefalopatías/metabolismo , Humanos , Modelos Neurológicos , Neuroglía/metabolismo , Neuronas/metabolismo , Serina/química , Serina/metabolismoRESUMEN
Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.
Asunto(s)
Envejecimiento/fisiología , Cicloserina/metabolismo , Hipocampo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Agonistas de Aminoácidos Excitadores/metabolismo , Hipocampo/anatomía & histología , Hipocampo/metabolismo , Ácido Kaínico/metabolismo , Potenciación a Largo Plazo , Masculino , Plasticidad Neuronal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Transmisión Sináptica/fisiología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments. Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methyl-D-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines.
Asunto(s)
Envejecimiento/fisiología , Hipocampo/fisiología , Magnesio/fisiología , Sinapsis/fisiología , Animales , Humanos , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.
Asunto(s)
Envejecimiento/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Neuroglía/metabolismo , Neurotransmisores/metabolismo , Serina/metabolismo , Animales , Sitios de Unión , Hipocampo/citología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Neurotransmisores/biosíntesis , Neurotransmisores/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/biosíntesis , Serina/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Factores de TiempoRESUMEN
Motherhood modifies the biology and behavior of the female, a process which prepares the mother's cognitive systems that are needed for nurturance. It has recently been shown that motherhood enhances hippocampal-mediated spatial learning and synaptic plasticity. Deleterious and long-term effects of a stress experienced during gestation have been demonstrated on progeny. Surprisingly little is known about the effect of such stress on mothers. Here, we investigated the effect of gestational stress on the adaptive changes due to motherhood. Female rats were mated and stressed during the last week of gestation. Two weeks after weaning, they were submitted to behavioral tests or electrophysiological study. A group of females were then kept for 16 months after motherhood experience to study the long-term effect of gestational stress and motherhood on memory when they were 22 months old. We confirm that a single motherhood experience selectively increases hippocampal-mediated spatial memory during the entire lifespan of female rats and protects them from age-associated memory impairments. However, we demonstrate that a stressful experience during gestation totally abolishes the positive effects of motherhood both on spatial memory and on hippocampal synaptic plasticity (long-term potentiation). Environmental factors that induce biological vulnerability have negative effects even for fundamental biological behaviors.
Asunto(s)
Memoria/fisiología , Madres , Plasticidad Neuronal/fisiología , Estrés Psicológico , Animales , Conducta Animal/fisiología , Electrofisiología , Femenino , Hipocampo/fisiología , Aprendizaje/fisiología , Esperanza de Vida , Masculino , N-Metilaspartato/metabolismo , Embarazo , Ratas , Ratas Wistar , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
The effects of the co-agonist of the N-methyl-D-aspartate receptor (NMDAr) D-serine on glutamatergic neurotransmission and synaptic potentiation were studied in the CA1 hippocampal field of young (3-5 months old) and aged (25-27 months old) Sprague-Dawley rats using ex vivo extracellular electrophysiological recording techniques. Exogenous d-serine depressed fast neurotransmission mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate subtype of glutamate receptors in young but not in aged rats by acting on inhibitory glycinergic interneurons. In contrast, D-serine dose-dependently enhanced NMDAr-mediated synaptic responses in both groups of animals, but with a larger magnitude in aged rats, thus preventing the age-related decrease in NMDAr activation. D-serine also increased the magnitude of long-term potentiation in aged but not in young rats. Finally, D-serine levels were dramatically reduced in hippocampal tissues of aged rats. Taken together, these results indicate a weaker activation of the NMDAr glycine modulatory site by endogenous D-serine in aged animals, which accounts for a reduced NMDAr contribution to synaptic plasticity in ageing.
Asunto(s)
Envejecimiento/fisiología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Serina/farmacología , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Electrofisiología , Ácido Glutámico/fisiología , Glicina/fisiología , Masculino , Red Nerviosa/fisiología , Ratas , Ratas Sprague-Dawley , Receptores AMPA/efectos de los fármacos , Receptores de Ácido Kaínico/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
1. The glycine-binding site of the glutamatergic N-methyl-d-aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist d-cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials. 2. We showed that DCS facilitated NMDAr-mediated synaptic potentials. In addition, we found that the magnitude of NMDAr-dependent long-term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered. 3. We found that DCS decreased neurotransmission mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the gamma-aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine. 4. These results, therefore, show opposite effects of DCS on NMDA and non-NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long-term synaptic plasticity that may support the DCS-induced enhanced cognitive performances.
Asunto(s)
Cicloserina/farmacología , Hipocampo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/efectos de los fármacos , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiología , Técnicas In Vitro , Masculino , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/fisiología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Receptores de Ácido Kaínico/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Transmisión Sináptica/fisiología , Factores de TiempoRESUMEN
We have investigated the role of somatostatin receptor subtypes sst2 and sst4 in limbic seizures and glutamate-mediated neurotransmission in mouse hippocampus. As compared to wild-type littermates, homozygous mice lacking sst2 receptors showed a 52% reduction in EEG ictal activity induced by intrahippocampal injection of 30 ng kainic acid (P < 0.05). The number of behavioural tonic-clonic seizures was reduced by 50% (P < 0.01) and the time to onset of seizures was doubled on average (P < 0.05). Seizure-associated neurodegeneration was found in the injected hippocampus (CA1, CA3 and hilar interneurons) and sporadically in the ipsilateral latero-dorsal thalamus. This occurred to a similar extent in wild-type and sst2 knock-out mice. Intrahippocampal injection of three selective sst2 receptor agonists in wild-type mice (Octreotide, BIM 23120 and L-779976, 1.5-6.0 nmol) did not affect kainate seizures while the same compounds significantly reduced seizures in rats. L-803087 (5 nmol), a selective sst4 receptor agonist, doubled seizure activity in wild-type mice on average. Interestingly, this effect was blocked by 3 nmol octreotide. It was determined, in both radioligand binding and cAMP accumulation, that octreotide had no direct agonist or antagonist action at mouse sst4 receptors expressed in CCl39 cells, up to micromolar concentrations. In hippocampal slices from wild-type mice, octreotide (2 micro m) did not modify AMPA-mediated synaptic responses while facilitation occurred with L-803087 (2 micro m). Similarly to what was observed in seizures, the effect of L-803087 was reduced by octreotide. In hippocampal slices from sst2 knock-out mice, both octreotide and L-803087 were ineffective on synaptic responses. Our findings show that, unlike in rats, sst2 receptors in mice do not mediate anticonvulsant effects. Moreover, stimulation of sst4 receptors in the hippocampus of wild-type mice induced excitatory effects which appeared to depend on the presence of sst2 subtypes, suggesting these receptors are functionally coupled.
Asunto(s)
Hipocampo/metabolismo , Receptores de Somatostatina/metabolismo , Convulsiones/metabolismo , Animales , AMP Cíclico/metabolismo , Susceptibilidad a Enfermedades , Electroencefalografía , Electrofisiología , Epilepsia/metabolismo , Hipocampo/fisiopatología , Masculino , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/genética , Convulsiones/fisiopatología , Transmisión SinápticaRESUMEN
Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered. Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.
Asunto(s)
Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal/genética , Receptores de Somatostatina/deficiencia , Conducta Espacial/fisiología , Animales , Conducta Animal , Condicionamiento Operante , Aprendizaje Discriminativo/fisiología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/fisiología , Técnicas In Vitro , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Noqueados , Motivación , Inhibición Neural/fisiología , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Somatostatina/genética , Sinapsis/fisiologíaRESUMEN
The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP) to the synaptic plasticity was investigated in hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice. We showed that long-term potentiation (LTP) induced by tetanic stimulation in CaBP-deficient mice was impaired. The fundamental biophysical properties of NMDA receptors and their number were not modified in CaBP-deficient mice. We also demonstrated that the physiological properties of calcium channels were identical between genotypes. An insufficient Ca(2+) entry through NMDA receptors or calcium channels, or a decrease in NMDA receptor density are unlikely to explain this impairment of LTP. Interestingly, we showed that the loss of LTP was not prevented by glycine but was restored in the presence of a low concentration of the NMDA receptor antagonist D-APV (5 microM) and of the calcium chelator BAPTA-AM (5 microM). Moreover, we observed a loss of LTP in the wild-type mice when the postsynaptic tetanic-induced [Ca(2+)](i) rise is excessively increased. Conversely, a weaker tetanus stimulation allowed LTP induction and maintenance in CaBP-deficient mice. These results suggest that a higher cytosol [Ca(2+)](i), due to the decrease of CaBP expression may impair LTP induction and maintenance mechanisms without affecting the mechanisms of calcium entry. Thus, CaBP plays a critical role in long term synaptic plasticity by limiting the elevation of calcium rise in the cytosol to some appropriate spatio-temporal pattern.
Asunto(s)
Canales de Calcio/fisiología , Potenciación a Largo Plazo/genética , Receptores de N-Metil-D-Aspartato/fisiología , Proteína G de Unión al Calcio S100/genética , Animales , Sitios de Unión/genética , Calbindinas , Canales de Calcio/genética , Canales de Calcio/metabolismo , Masculino , Ratones , Ratones Transgénicos , Plasticidad Neuronal/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Proteína G de Unión al Calcio S100/fisiologíaRESUMEN
Age-related alterations of N-methyl-D-aspartate receptor (NMDAr) activation were investigated in the CA1 field of hippocampal slices from young (3-6 months old) and aged (25-33 months old) Sprague-Dawley rats by using ex vivo extracellular electrophysiological recording techniques. NMDAr-mediated field excitatory postsynaptic potentials (fEPSPs) were induced by electrical stimulation of glutamatergic fibers in a magnesium (Mg(2+))-free medium supplemented with the non-NMDAr antagonist CNQX. The fEPSPs were significantly smaller in aged rats, whereas the response of presynaptic afferent fibers remained unaffected. No significant age-related differences were found in the ability of Mg(2+) to depress the magnitude of NMDAr-mediated fEPSPs. The responsiveness of postsynaptic NMDAr to the agonist was assessed in both groups of animals. No age-related differences were recorded either in the depolarizing effect of bath-applied NMDA or in the magnitude of the depolarization after altering extracellular Mg(2+) concentration. Finally, short-term potentiation (STP) of excitatory transmission was studied in young and aged rats considering the pivotal role of NMDAr in synaptic plasticity. No age-related alterations of the magnitude and the time course of STP in response to 10 or 30Hz conditioning stimulation were found. Because of the decrease in the magnitude of NMDAr-mediated synaptic transmission in aged animals, the absence of obvious modifications of synaptic plasticity suggests the occurrence of compensatory mechanisms that are discussed.