One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected b...One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings.展开更多
With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate recept...With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.展开更多
Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the me...Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17, 展开更多
Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulati...Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cog-nition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China(appr展开更多
Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifica...Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.展开更多
Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists...Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in ord展开更多
Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic ...Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.展开更多
The prefrontal cortex （PFC） is thought to store the traces for a type of long-term memory - the memory that determines the temporal structure of behavior often termed a ＂rule＂ or ＂strategy＂. Long-term synaptic p...The prefrontal cortex （PFC） is thought to store the traces for a type of long-term memory - the memory that determines the temporal structure of behavior often termed a ＂rule＂ or ＂strategy＂. Long-term synaptic plasticity might serve as an underlying cellular mechanism for this type of memory. We therefore studied the induction of synaptic plasticity in rat PFC neurons, maintained in vitro, with special emphasis on the functionally important neuromodulator dopamine. First, the induction of long-term potentiation （LTP） was facilitated in the presence of tonic/background dopamine in the bath, and the dose-dependency of this background dopamine followed an ＂inverted-U＂ function, where too high or too low dopamine levels could not facilitate LTP. Second, the induction of long-term depression （LTD） by low-frequency stimuli appeared to be independent of background dopamine, but required endogenous, phasically-released dopamine during the stimuli. Blockade of dopamine receptors during the stimuli and exaggeration of the effect of this endogenouslyreleased dopamine by inhibition of dopamine transporter activity both blocked LTD. Thus, LTD induction also followed an inverted-U function in its dopamine-dependency. We conclude that PFC synaptic plasticity is powerfully modulated by dopamine through inverted-U-shaped dose-dependency.展开更多
Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,...Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,with impaired LTP found to be associated with AD.However,the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated.Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear.Herein,we induced LTP in the hippocampal CA1 region of wildtype(WT)and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region.We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes(DEGs)in mice with normal LTP,and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP.We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction.Among them,we found that the expression of Pygm,which catabolizes glycogen,was also decreased in AD patients.We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice,while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice.Moreover,we showed that PYGM directly regulated energy generation in neurons.Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function,but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.展开更多
Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp 120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techn...Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp 120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2＋ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gpl20 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.展开更多
Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is...Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sym-pathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentialtion at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.展开更多
Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events tha...Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events that haven’t been studied in the mature rat hippocampus. In our studies, we used hippocampal preparations from juvenile (14 - 25 days) and mature (60 - 90 days) rats to assess insulin modulation of CA1 synaptic transmission and AMPAR trafficking and phosphorylation. Using field potential electrophysiology, we observed that insulin induced LTD in the juvenile hippocampus (as previously reported) in the presence and absence of phosphoinositide 3-kinase (PI3K) activity, but produced no significant long-term changes in the mature hippocampus in the presence of PI3K activity. Interestingly, during PI3K inhibition, insulin did produce LTD in the mature hippocampus. Additionally, insulin induced a long-term decrease in plasma membrane expression of the GluA2 and GluA1 subunits of the AMPAR in the juvenile, but not mature hippocampus. Furthermore, there was a long-term decrease in GluA1 phosphorylation at Serine 845 in the juvenile, but not mature hippocampus. These data reveal that insulin modulation of synaptic plasticity and AMPAR modulation within the hippocampus is age-dependent, suggesting that insulin-regulated behaviors may also show age-dependence. These findings are important largely due to the increased use of insulin as a therapeutic throughout the lifespan. Our data suggest that additional work should be done to determine how this use of insulin throughout different stages of life might affect synaptic function and development.展开更多
基金supported by the National Basic Research Program of China (Grant No 2006CB806600)the Knowledge Innovation Program of the Chinese Academy of Sciences (Grant No KSCX2-YW-R-29)
文摘One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings.
基金supported by the National Natural Science Foundation of China(61401497)
文摘With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.
基金supported by the National Natural Science Foundation of China,No.81571038,81771145(both to YZ)
文摘Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17,
基金supported by the National Natural Science Foundation of China,No.81272156(to TCG)
文摘Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cog-nition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China(appr
基金supported by the National Natural Science Foundation of China,Nos.81925031(to YT),81820108026(to YT),81972967(to WJL),81872549(to YL)the Youth Program of National Natural Science Foundation of China,No.81801229(to YTX)+3 种基金a grant from Guangdong Science and Technology Department of China,Nos.2020B1212060018(to WJL),2020B1212030004(to WJL)the Natural Science Foundation of Guangdong Province,No.2019A1515011754(to WJL)the Science and Technology Program of Guangzhou of China,No.202007030001(to YT)the Science and Technology Planning Project of Guangzhou of China,No.201704030033(to YL).
文摘Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.
文摘Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in ord
基金supported by the National Natural Science Foundation of China,No.81971246 (to TM)Opening Foundation of Jiangsu Key Laboratory of Neurodegeneration,Nanjing Medical University,No.KF202204 (to LZ and SF)。
文摘Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.
文摘The prefrontal cortex （PFC） is thought to store the traces for a type of long-term memory - the memory that determines the temporal structure of behavior often termed a ＂rule＂ or ＂strategy＂. Long-term synaptic plasticity might serve as an underlying cellular mechanism for this type of memory. We therefore studied the induction of synaptic plasticity in rat PFC neurons, maintained in vitro, with special emphasis on the functionally important neuromodulator dopamine. First, the induction of long-term potentiation （LTP） was facilitated in the presence of tonic/background dopamine in the bath, and the dose-dependency of this background dopamine followed an ＂inverted-U＂ function, where too high or too low dopamine levels could not facilitate LTP. Second, the induction of long-term depression （LTD） by low-frequency stimuli appeared to be independent of background dopamine, but required endogenous, phasically-released dopamine during the stimuli. Blockade of dopamine receptors during the stimuli and exaggeration of the effect of this endogenouslyreleased dopamine by inhibition of dopamine transporter activity both blocked LTD. Thus, LTD induction also followed an inverted-U function in its dopamine-dependency. We conclude that PFC synaptic plasticity is powerfully modulated by dopamine through inverted-U-shaped dose-dependency.
基金supported by the National Natural Science Foundation of China (U21A20361 and 82130039 to Y.W.Z.)Fundamental Research Funds for the Central Universities (20720220133 to Y.W.Z.)+2 种基金Natural Science Foundation of Fujian Province (2021J02057 to Q.L.M.)Science and Technology Plan Projects of Fujian Province (2020Y2015 to Z.X.W.)2020 Joint Support of Key Projects on Health Care (3502Z20209005 to Z.X.W.)。
文摘Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,with impaired LTP found to be associated with AD.However,the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated.Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear.Herein,we induced LTP in the hippocampal CA1 region of wildtype(WT)and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region.We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes(DEGs)in mice with normal LTP,and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP.We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction.Among them,we found that the expression of Pygm,which catabolizes glycogen,was also decreased in AD patients.We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice,while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice.Moreover,we showed that PYGM directly regulated energy generation in neurons.Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function,but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.
基金supported by the National Natural Science Foundation of China,No.81171134 and 81471235a grant from the Introducing Talents of Discipline to Universities,No.B14036+4 种基金a grant from the College Students’Extracurricular Scientific Innovation and Entrepreneurial Activity Research Topic of Jinan University Challenge Cup,No.(2013)27 and (2014)16a grant from the College Students’Extracurricular Scientific Innovation and Entrepreneurial Activity Research Topic of Jinan University in China,No.201410559079,1055914162 and CX14261a grant from the National Basic Research Program of China(973 Program),No.2011CB707501the Science and Technology Foundation of Guangdong Province in China,No.2010B030700016the Natural Science Foundation of Guangdong Province in China,No.2014A030313360
文摘Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp 120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2＋ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gpl20 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.
文摘Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sym-pathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentialtion at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.
文摘Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events that haven’t been studied in the mature rat hippocampus. In our studies, we used hippocampal preparations from juvenile (14 - 25 days) and mature (60 - 90 days) rats to assess insulin modulation of CA1 synaptic transmission and AMPAR trafficking and phosphorylation. Using field potential electrophysiology, we observed that insulin induced LTD in the juvenile hippocampus (as previously reported) in the presence and absence of phosphoinositide 3-kinase (PI3K) activity, but produced no significant long-term changes in the mature hippocampus in the presence of PI3K activity. Interestingly, during PI3K inhibition, insulin did produce LTD in the mature hippocampus. Additionally, insulin induced a long-term decrease in plasma membrane expression of the GluA2 and GluA1 subunits of the AMPAR in the juvenile, but not mature hippocampus. Furthermore, there was a long-term decrease in GluA1 phosphorylation at Serine 845 in the juvenile, but not mature hippocampus. These data reveal that insulin modulation of synaptic plasticity and AMPAR modulation within the hippocampus is age-dependent, suggesting that insulin-regulated behaviors may also show age-dependence. These findings are important largely due to the increased use of insulin as a therapeutic throughout the lifespan. Our data suggest that additional work should be done to determine how this use of insulin throughout different stages of life might affect synaptic function and development.
