RESUMEN
Although L-type voltage-dependent calcium channels (VDCCs) have been reported to display different even contrary actions on cognitive functions and long-term potentiation (LTP) formation, there is little information regarding the role of L-type VDCCs in behavioral LTP, a learning-induced LTP model, in the intact brain of freely behaving animals. Here we investigated the effects of verapamil, a non-selective blocker of L-type VDCCs, on behavioral LTP and cognitive functions. Population spikes (PS) were recorded by using electrophysiological methods to examine the role of verapamil in behavioral LTP in the hippocampal dentate gyrus (DG) region. Y-maze assay was used to evaluate the effects of verapamil on learning and memory. Electron microscope was used to observe the changes on synaptic ultrastructural morphology in hippocampal DG area. We found that intrahippocampal verapamil treatments had no significant changes on the PS amplitude during a 90min recordings period. However, intrahippocampal applications of verapamil, including pre- or post-training, reduced behavioral LTP magnitude and memory retention but did not prevent the induction of behavioral LTP and the acquisition of learning. The saline group with behaving trainings showed obvious increases in the number of smile synapses, the length of active zones and the thickness of postsynaptic density as compared to the baseline group, but verapamil with pre-training treatment almost returned these changes to the baseline levels except for the synaptic interface curvature. In conclusion, our results suggest that L-type VDCCs may only contribute to the magnitude of behavioral LTP and the memory maintenance with an activity-independent relationship. L-type VDCCs may be critical to new information long-term storage rather than acquisition in hippocampus.
Asunto(s)
Canales de Calcio Tipo L/fisiología , Giro Dentado/fisiología , Potenciación a Largo Plazo , Retención en Psicología/fisiología , Animales , Bloqueadores de los Canales de Calcio/administración & dosificación , Giro Dentado/efectos de los fármacos , Giro Dentado/ultraestructura , Masculino , Ratas Sprague-Dawley , Sinapsis/ultraestructura , Verapamilo/administración & dosificaciónRESUMEN
Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.
RESUMEN
Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS. Furthermore, we found that 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptors antagonist, could block the roles of cordycepin on LTD and LTP. Collectively, cordycepin was able to modulate metaplasticity in hippocampal CA1 area of rats through adenosine A1 receptors. These findings would be helpful to reconcile the conflicting reports in the literatures and provided new insights into the mechanisms underlying cognitive function promotions with cordycepin treatment.
Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Desoxiadenosinas/farmacología , Plasticidad Neuronal/efectos de los fármacos , Receptor de Adenosina A1/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Región CA1 Hipocampal/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Receptor de Adenosina A1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Tenuigenin (TEN), a natural product from the Chinese herb Polygala tenuifolia root, has been reported to improve cognitive function and exhibits neuroprotective effects in pharmacological studies of the central nervous system. Synaptic transmission is the essential process of brain physiological functions such as learning and memory formation, and TEN has been shown to facilitate the basic synaptic transmission. HYPOTHESIS/PURPOSE: Although our previous work has demonstrated that TEN is able to potentiate the basic synaptic transmission, the potential mechanism remains unclear. Here we investigated the effect of TEN on the synaptic transmission and analysed the potential mechanism. We hope that these findings will contribute to explain the role of TEN as a nootropic product or neuroprotective drug in the future. METHODS: Field excitatory postsynaptic potentials (fEPSPs), spontaneous excitatory postsynaptic currents (sEPSCs) and miniature spontaneous excitatory postsynaptic currents (mEPSCs) were recorded, by using in vitro field potential electrophysiology and whole-cell patch clamp techniques in acute hippocampal slices from rats. RESULTS: TEN perfusion significantly enhanced the slope of fEPSPs and reduced the ratio of paired-pulse facilitation. Moreover, TEN increased the frequency and amplitude of sEPSCs but only improved the frequency of mEPSCs rather than amplitude in hippocampal CA1 pyramidal neurons. With removal of extracellular calcium, TEN treatment also enhanced the mEPSCs frequency without affecting amplitude. Interestingly, the increase of mEPSCs frequency caused by TEN was blocked by chelation of intracellular calcium with BAPTA-AM. CONCLUSION: These results indicate that TEN enhances the basic synaptic transmission via stimulating presynaptic intracellular calcium.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Calcio/metabolismo , Medicamentos Herbarios Chinos/farmacología , Potenciales Postsinápticos Excitadores , Transmisión Sináptica/efectos de los fármacos , Animales , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND PURPOSE: Schizandrin (SCH) has been reported to prevent or reduce learning and memory defects. However, it is not known whether SCH ameliorates cognitive impairments induced by oestrogen deficiency. In the present study, we investigated the effect of SCH on memory in ovariectomized (OVX) and non-OVX rats. EXPERIMENTAL APPROACH: A passive avoidance test was used to evaluate the effect of SCH on memory. Field EPSPs were recorded in hippocampal slices using an electrophysiological method. In OVX rats, biochemical parameters in the bilateral hippocampus were measured; these included superoxide dismutase (SOD), malondialdehyde (MDA) and AChE. Also, the number of NADPH-diaphorase (NADPH-d) positive neurons was counted by NADPH-d histochemistry staining technique. KEY RESULTS: Oral SCH improved the memory and facilitated the induction of long-term potentiation in non-OVX and OVX rats; this effect was more obvious in OVX rats. Similarly, SCH perfusion enhanced synaptic transmission in hippocampal slices from both non-OVX and OVX rats. However, SCH perfusion reduced the ratio of paired-pulse facilitation only in OVX but not in non-OVX rats. In addition, SCH decreased AChE activity and MDA level and increased SOD activity and the number of NADPH-d-positive neurons in OVX rats. CONCLUSIONS AND IMPLICATIONS: SCH improves memory in OVX rats and its potential mechanisms may include a reduction in the loss of hippocampal NADPH-d positive neurons, an increase of antioxidant properties and a potentiation of synaptic transmission that possibly involves to enhance cholinergic function. Overall, our findings indicate that SCH has potential as a therapeutic strategy for the cognitive dysfunctions associated with the menopause.
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Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Hipocampo/efectos de los fármacos , Lignanos/farmacología , Lignanos/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Ovariectomía/efectos adversos , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Transmisión Sináptica/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Reacción de Prevención/efectos de los fármacos , Recuento de Células , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Proteínas Ligadas a GPI/metabolismo , Hipocampo/anatomía & histología , Hipocampo/metabolismo , Hipocampo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Malondialdehído/metabolismo , Trastornos de la Memoria/inducido químicamente , Ratas , Superóxido Dismutasa/metabolismoRESUMEN
PURPOSE: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. METHODS: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. RESULTS: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. CONCLUSIONS: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission.
RESUMEN
AIMS: Cordycepin plays an important role in modulating the function of central nervous system (CNS). However, the modulating mechanism is poorly understood. Excitatory synaptic transmission, the essential process in brain physiology and pathology, is critical in the signal integration activities of the CNS. To further understand the effects of cordycepin on CNS, we investigated the effects of cordycepin on excitatory synaptic transmission in the CA1 region of rat hippocampal slices. METHODS: The effects of cordycepin on excitatory synaptic transmission were investigated by using in vitro field potential electrophysiology and whole-cell patch clamp techniques. RESULTS: Cordycepin significantly decreased the amplitudes of field excitatory postsynaptic potentials (fEPSPs) elicited in the CA1 by stimulation of the Schaffer-commissural fibers. And the reduction in fEPSPs amplitude was associated with an increase in the paired-pulse facilitation. Cordycepin also suppressed α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated responses but did not directly affect AMPA receptors and NMDA receptors. Furthermore, quantal analysis revealed that cordycepin decreased the frequency but not amplitude of miniature spontaneous excitatory postsynaptic currents. CONCLUSIONS: These results demonstrate that cordycepin suppresses excitatory synaptic transmission by decreasing the excitatory neurotransmitter release presynaptically, which provides an evidence for the novel potential mechanism of cordycepin in modulating the function of CNS.
Asunto(s)
Desoxiadenosinas/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiología , Técnicas de Cultivo de Órganos , Terminales Presinápticos/fisiología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Polygala tenuifolia root has been used to improve memory and cognitive function in Traditional Chinese Medicine for more than 2000 years. Since tenuigenin (TEN) is one of the most utilized P. tenuifolia root extracts, it is surprising there is no evidence for the effects of TEN on learning and memory so far. In the present study, we investigated the effects of TEN on learning and memory with Y-maze test in mice. We found that oral administration of 4mg/kg TEN significantly improved learning and memory in Y-maze task. Treatment with 4mg/kg TEN markedly reduced the acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and increased superoxide dismutase (SOD) activity in hippocampus. In the electrophysiological test of hippocampal brain slice, 2µg/ml TEN perfusion substantially enhanced field excitatory postsynaptic potential (fEPSP) amplitude both in basic synaptic transmission and after high frequency stimulation (HFS) in Schaffer to CA1 pathway (Scha-CA1). These results indicate that TEN enhancing learning and memory may result from inhibiting AChE activity, improving antioxidation and enhancing synaptic plasticity in mice. Therefore, TEN shows promise as a potential nootropic product in improving learning and memory.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Nootrópicos/farmacología , Acetilcolinesterasa/metabolismo , Animales , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Especificidad de la Especie , Superóxido Dismutasa/metabolismo , Factores de TiempoRESUMEN
Cordycepin (3'-deoxyadenosine) is the main functional component of Cordycepins militaris, a renowned traditional Chinese medicine, which has been shown to possess anti-tumor, anti-inflammatory, anti-diabetic and neuro-protective effects. However, the effect of cordycepin on the central nervous system (CNS) remains unclear. In this study, the effects of cordycepin on neuronal activity were investigated on the CA1 pyramidal neurons in rat hippocampal brain slices using a whole-cell patch clamp technique. Our results revealed that cordycepin significantly decreased the frequency of both the spontaneous and evoked action potential (AP) firing. While AP spike width, the amplitude of fast after hyperpolarization (fAHP), and membrane input resistance were not altered by cordycepin, the neuronal membrane potential was hyperpolarized by cordycepin. Collectively, these results demonstrate that cordycepin reduces neuronal activity by inducing membrane hyperpolarization, indicating that cordycepin may be a potential therapeutic strategy for ischemic and other excitotoxic disorders.