Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease

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.

Effects of electroacupuncture versus nimodipine on long-term potentiation and synaptophysin expression in a rat model of vascular dementia

The present study stimulated Baihui （DU 20） and Dazhui （DU 14） acupoints in a rat model of vascular dementia with electroacupuncture to investigate changes in long-term potentiation and synaptophysin expression in the hippocampus. The results revealed that synaptophysin expression in brain tissues was increased after electroacupuncture. After high4requency stimulation, the population spike latency was shortened and the excitatory postsynaptic potential slope and population spike amplitude were increased. In addition, cognitive function was enhanced, similar to the effects of intragastric perfusion of nimodipine. The results indicated that electroacupuncture at Baihui and Dazhui acupoints can improve learning and memory functions of a rat model of vascular dementia by promoting synaptophysin expression, enhancing hippocampal synaptic plasticity and accelerating synaptic transmission.

Aniracetam attenuates H_2O_2-induced deficiency of neuron viability, mi-tochondria potential and hippocampal long-term potentiation of mice in vitro

Objective It is known that free radicals are involved in neurodegeneration and cognitive dysfunction, as seen in Alzheimer＇s disease （AD） and aging. The present study examines the protective effects of aniracetam against H2O2- induced toxicity to neuron viability, mitochondria potential and hippocampal long-term potentiation （LTP）. Methods Tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide （MTT） was used to detect neuronal viability. MitoTracker Red （CMX Ros）, a fluorescent stain for mitochondria, was used to measure mitochondria potential. Electrophysiological technique was carried out to record hippocampual LTE Results H2O2 exposure impaired the viability of neurons, reduced mitochondria potential, and decreased LTP in the CA region of hippocampus. These deficient effects were significantly rescued by pre-treatment with aniracetam （10 ～100μmol/L）. Conclusion These results indicate that aniracetam has a strong neuroprotective effect against H2O2-induced toxicity, which could partly explain the mechanism of its clinical application in neurodegenerative diseases.

3'-Deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome

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.

Active fraction combination from Liuwei Dihuang decoction(LW-AFC) ameliorates corticosterone-induced long-term potentiation impairment in mice in vivo

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 order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS Chronic administration(ig) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration(icv, ig, ip) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration(ig, ip) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate;there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals’ hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.

Effects of Exposure to Aluminum on Long-term Potentiation and AMPA Receptor Subunits in Rats in vivo

Objective To explore the effects of exposure to aluminum （AI） on long-term potentiation （LTP） and AMPA receptor subunits in rats in vivo. Methods Different dosages of aluminum-maltolate complex [Al（mal）3] were given to rats via acute intracerebroventricular （i.c.v.） injection and subchronic intraperitoneal （i.p.） injection. Following AI exposure, the hippocampal LTP were recorded by field potentiation technique in vivo and the expression of AMPAR subunit proteins （GluR1 and GluR2） in both total and membrane-enriched extracts from the CA1 area of rat hippocampus were detected by Western blot assay. Results Acute AI treatment produced dose-dependent suppression of LTP in the rat hippocampus and dose-dependent decreases of GluRz and GluR2 in membrane extracts; however, no similar changes were found in the total cell extracts, which suggests decreased trafficking of AMPA receptor subunits from intracellular pools to synaptic sites in the hippocampus. The dose-dependent suppressive effects on LTP and the expression of AMPA receptor subunits both in the membrane and in total extracts were found after subchronic AI treatment, indicating a decrease in AMPA receptor subunit trafficking from intracellular pools to synaptic sites and an additional reduction in the expression of the subunits. Conclusion Al（mal）3 obviously and dose-dependently suppressed LTP in the rat hippocampal CA1 region in vivo, and this suppression may be related to both trafficking and decreases in the expression of AMPA receptor subunit proteins. However, the mechanisms underlying these observations need further investigation.

Hippocampal ischemia causes deficits in local field potential and synaptic plasticity

The long-term enhancement in glutamate receptor mediated excitatory responses has been observed in stroke model. This pathological form of plasticity, termed post-ischemic long-term potentiation （i-LTP）, points to functional reorganization after stroke. Little is known, however, about whether and how this i-LTP would affect subsequent induction of synaptic plasticity. Here, we first directly confirmed that i-LTP was induced in the endothelin-l-induced ischemia model as in other in vitro models. We also demonstrated increased expression of NR2B, CaMKII and p-CaMKII, which are reminiscent of i-LTP. We further induced LTP of field excitatory post- synaptic potentials （fEPSPs） on CA1 hippocampal neurons in peri-infarct regions of the endothelin-l-induced mini-stroke model. We found that LTP of fEPSPs, induced by high-frequency stimulation, displayed a progressive impairment at 12 and 24 hours after ischemia. Moreover, using in vivo multi-channel recording, we found that the local field potential, which represents electrical property of cell ensembles in more restricted regions, was also dam- pened at these two time points. These results suggest that i-LTP elevates the induction threshold of subsequent synap- tic plasticity. Our data helps to deepen the knowledge of meta-synaptic regulation of plasticity after focal ischemia.

The RAS/PI3K Pathway is Involved in the Impairment of Long-term Potentiation Induced by Acute Aluminum Treatment in Rats

Objective To explore the role of RAS/PI3K pathway in the impairment of long-term potentiation （LTP） induced by acute aluminum （AI） treatment in rats in vivo. Methods First, different dosages of aluminum-maltolate complex [Al（mal）3] were given to rats via acute intracerebroventricular （i.c.v.） injection. Following AI exposure, the RAS activity of rat hippocampus were detected by ELISA assay after the hippocampal LTP recording by field potentiation technique in vivo. Second, the antagonism on the aluminum-induced suppression of hippocampal LTP was observed after the treatment of the RAS activator epidermal growth factor （EGF）. Finally, the antagonism on the downstream molecules （PKB activity and the phosphorylation of GluR1 $831 and $845） were tested by ELISA and West-blot assays at the same time. Results With the increasing aluminum dosage, a gradually decreasing in RAS activity of the rat hippocampus was produced after a gradually suppressing on LTP. The aluminum-induced early suppression of hippocampal LTP was antagonized by the RAS activator epidermal growth factor （EGF）. And the EGF treatment produced changes similar to those observed for LTP between the groups on PKB activity as well as the phosphorylation of GluR1 S831 and s845. Conclusion The RAS-PI3K/PKB-GluR1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats. However, the mechanisms underlying this observation need further investigation.

Effects of Chronic Administration of Melatonin on Spatial Learning Ability and Long-term Potentiation in Lead-exposed and Control Rats

Objective To explore the changes in spatial learning performance and long-term potentiation （LTP） which is recognized as a component of the cellular basis of learning and memory in normal and lead-exposed rats after administration of melatonin （MT） for two months. Methods Experiment was performed in adult male Wistar rats （12 controls, 12 exposed to melatonin treatment, 10 exposed to lead and 10 exposed to lead and melatonin treatment）. The lead-exposed rats received 0.2% lead acetate solution from their birth day while the control rats drank tap water. Melatonin （3 mg/kg） or vehicle was administered to the control and lead-exposed rats from the time of their weaning by gastric gavage each day for 60 days, depending on their groups. At the age of 81-90 days, all the animals were subjected to Morris water maze test and then used for extracellular recording of LTP in the dentate gyrus （DG） area of the hippocampus in vivo. Results Low dose of melatonin given from weaning for two months impaired LTP in the DG area of hippocampus and induced learning and memory deficit in the control rats. When melatonin was administered over a prolonged period to the lead-exposed rats, it exacerbated LTP impairment, learning and memory deficit induced by lead. Conclusion Melatonin is not suitable for normal and lead-exposed children.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer’s disease?

Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.

Electric stimulation at sciatic nerve evokes long-term potentiation of cornu dorsale medullae spinalis field potential in rats at various developmental phases

BACKGROUND： Long-term potentiation of cornu dorsale medullae spinalis field potential in adult rats has already been reported; however, there is lack of correlated researches on naenonate, infant and adult rats which have different responses to pain conduction information.OBJECTIVE： To observe the various effects of electric stimulation at sciatic nerve on long-term potentiation of evoked field potential at superficial layer of cornu dorsale medullae spinalis of rats at various developmental phases and analyze manifestations of pain conduction information at superficial layers （ Ⅰ - Ⅱ）of cornu dorsale medullae spinalis in immature rats.DESIGN： Grouping controlled study.SETTING： Department of Physiology, Medical College of Wuhan University.MATERIALS： The experiment was carried out in the Laboratory of Physiology （provincial laboratory）,Medical College of Wuhan University from March 2006 to May 2007. A total of 27 healthy male Sprague-Dawley （SD） rats, 17- 90 days old, SPF grade, weighing 41 -200 g, were provided by Experimental Animal Center, Medical College of Wuhan University.METHODS： Based on their birthdays, rats were divided into naenonate group （17 - 20 days old, weighing 41-52 g, n =10）, infant group （35 - 50 days old, weighing 87 - 125 g, n =10） and adult group （60 - 90 days old, weighing 180 -200 g, n =7）. Left sciatic nerve was separated and stimulated with single square wave （15 V, 0.5 ms）. Meanwhile, evoked field potential was recorded at superficial layers of lateral T13 - L1 cornu dorsale medullae spinalis and then stimulated with high-frequent and high-intensive tetanizing current （30 -40 V, 0.5 ms, 100 Hz, 1s per bundle, 10s in bundle interval） four times. After the operation, onset of long-term potentiation was observed; meanwhile, amplitude changes and latency of field potential were analyzed.MAIN OUTCOME MEASURES： Amplitude and latency changes of field potential at superficial layers of cornu dorsale medullae spinalis of rats in the three groups.RESULTS： A total of 27 accepted rats were involved in the final analysis. ① Amplitude changes： Electric stimulation at sciatic nerve with high-frequent and high-intensive tetanizing current could induce evoked field potential at superficial layers （Ⅰ-Ⅱ ） of cornu dorsale medullae spinalis in the three groups.Long-term potentiation in the naenonate group manifested that amplitude of A-kind never fiber was raised and there was significant difference （P〈0.05）. In addition, average amplitude was increased and there was obviously significant difference （P〈0.01）. Long-term potentiation in the infant group manifested that amplitude of C-kind never fiber was raised and there was significant difference （P〈0.01）; while, long-term potentiation in the adult group manifested that amplitude of C-kind never fiber was raised and there was significant difference （P〈0.01）. Otherwise, latencies in the three groups were all shortened. ② Latency changes： Average latency of A-kind nerve fiber in the naenonate group was shortened and there was significant difference （P〈0.01）; in addition, evoked potential of C-kind nerve fiber was low and latency was immovable. There was no significant difference before and after high-frequent and high-intensive electric stimulation （P〉0.05）. Average latency of C-kind nerve fiber in the infant group was shortened and there was significant difference （P〈0.01）; in addition, evoked potential of A-kind nerve fiber was stable and latency was immovable. There was no significant difference before and after high-frequent and high-intensive electric stimulation （P〉0.05）. Average latency of C-kind nerve fiber in the adult group was shortened and there was significant difference （P〈0.01）; in addition, evoked potential of A-kind nerve fiber was stable and latency was immovable. There was no significant difference before and after high-frequent and high-intensive electric stimulation.CONCLUSION： Evoked field potential at superficial layer of comu dorsale medullae spinalis can be recorded through electric stimulation at sciatic nerve. Single stimulation and tetanizing electric stimulation can cause different characteristics of evoked field potential in rats at various developmental phases.Superficial layer of cornu dorsale medullae spinalis of naenonate rats is mainly caused by A-kind nerve fiber which participants in pain conduction and formation of pain sensitivity; however, that of infant and adult rats mainly depends on C-kind nerve fiber.

Effect of Aluminum on Long-Term Potentiation and Its Relation to L-arg-No-pathway in Hippocampal CA3 Area of Rats

Experiments were performed on 64 Sprague-Dawley rats under ure-thane anesthesia. Extracellular recording method was used to investigate the effect of aluminum (Al)microinjected into CA3 on long-term potentiation (LTP) in this area. The relationship between the inhibitory effect of Al and L-arginine-NO pathway was also studied. Microinjection of Al (0. 5 mol/L, 1 μl ) into CA3 could block the induction of LTP in CA3. Microinjection of Al (0. 5 mol/L, 1 μl) into CA3 after LTP was induced could also decrease the amplitude of population spike (PS). The inhibitory effect of Al on LTP in CA3 could be enhanced by preinjection of NG-nitro-L-arginine (0. 3 mol/L, 1 μl). Preinjection of L-arginine (0. 3 mol/L, 1 μl) into CA3 could antagonize the inhibitory effect of Al on LTP. These results suggest that Al could block the induction of LTP and decrease the amplitude of PS potentiated in CA3. The effect of Al might be antagonized by L-arginine-NO pathway.

LW-AFC and its active components ameliorate corticosterone-induced long-term potentiation impairment in mice

OBJECTIVE LW-AFC is extracted from the classical traditional Chinese medicinal prescription-Liuwei Dihuang Decoction.Previous studies have showed that LW-AFC could improve learning&memory ability in amny animal models.In this study,we focused on evaluating the effect of several main active components fromLW-AFC(B-B;loganin,LOG;morroniside,MOR;paeoniflorin,PF and stachyose,STA)on LTP.METHODS In vivo recording of LTP was used in this study to evaluate the effects of LW-AFC and it′s active components on coticorsterone(Cort)induced LTP impairment.RESULTS The results showed that LW-AFC could ameliorate Cort-induced LTP impairment.The effect of LW-AFC was abolished when the immune function was inhibited.Single administration(ig,ip,icv)of any of the components had no effect on Cort-induced LTP impairment.Consecutively intragastric administration or intraperitoneal injections(chronic administration)of B-B,LOG,MOR or PF for 7 d showed protective effect on Cort-induced LTP impairment.Intragastric administration of STA for 7 d protected LTP from impairment induced by Cort,while there was little improving effect when STA was administrated via intraperitoneal injection.In addition,when the intestinal microbiota was disrupted by applying the antibiotic cocktail,STA showed little protective effect against Cort.CONCLUSION In conclusion,LW-AFC and it′s components showed positive effects against cort induced LTP impairment,it seems that all displayed protective effects via indirectly,immune modulation might be the common pathway for all components;the exact pathways are different in each component,B-B,LOG,MOR and PF could be absorbed into the bloods tream and then modulate the peripheral immune function,while STA could not be absorbed and modulates the immune function via modulating intestinal microbiota.Further studies are needed to invesgate the underlying mechanisms and the synergetic effects of all components.

Mechanisms of active fraction combination from Liuwei Dihuang Decoction(LW-AFC) on long-term potentiation impairment in vivo

OBJECTIVE Liuwei Dihuang Decoction(LW)-active fraction combination(LW-AFC,consist of 3 fractions polysaccharide,LWB-B;glycoside,LWD-b;oligosaccharide,CA-30)is extracted from LW,it is effective for the treatment of kidney yin deficiency in many animal models.This study evaluated the effects and mechanisms of LW-AFC and the active fractions 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 1h before the high-frequency stimulation(HFS)to induce LTP impairment.Moreover,in order to research on the possible effective pathways,an antibiotic cocktail and an immunosuppressant were also used.RESULTS Chronic administration(ig)of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Single administration(icv,ig,ip)of any of the active fractions had no effect on Cort-induced LTP impairment,while chronic administration(ig,ip)of LWB-B or LWD-b showed positive effects against Cort.Interestingly,CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition,when the intestinal microbiota was disrupted by application of the antibiotic cocktail,CA-30 showed little protective effects against Cort.The effects of LW-AFC were also abolished when the immune function was inhibited.In the hippocampal tissue,Cort treatment increased Cort and glutamate,and LW-AFC could inhibit the Cort-induced elevation of Cort and glutamate;there was little change in D-serine in Cort-treated animals,but LW-AFC could increase the D-serine levels.CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Their protective effects are unlikely by a direct way,and immune modulation might be the common pathway.CA-30 could protect LTP from impairment via modulating the intestinal microbiota.Decreasing Cort and glutamate and increasing D-serine in the Cort-treated animals'hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC.Further study is needed to understand the underlying mechanisms.

Correlating learning and memory improvements to long-term potentiation in patients with brain injury

BACKGROUND： Brain injury patients often exhibit learning and memory functional deficits. Long-term potentiation （LTP） is a representative index for studying learning and memory cellular models; the LTP index correlates to neural plasticity. OBJECTIVE： This study was designed to investigate correlations of learning and memory functions to LTP in brain injury patients, and to summarize the research advancements in mechanisms underlying brain functional improvements after rehabilitation intervention. RETRIEVAL STRATEGY： Using the terms ＂brain injuries, rehabilitation, learning and memory, long-term potentiation＂, manuscripts that were published from 2000-2007 were retrieved from the PubMed database. At the same time, manuscripts published from 2000-2007 were also retrieved from the Database of Chinese Scientific and Technical Periodicals with the same terms in the Chinese language. A total of 64 manuscripts were obtained and primarily screened. Inclusion criteria： studies on learning and memory, as well as LTP in brain injury patients, and studies focused on the effects of rehabilitation intervention on the two indices; studies that were recently published or in high-impact journals. Exclusion criteria： repetitive studies. LITERATURE EVALUATION： The included manuscripts primarily focused on correlations between learning and memory and LTP, the effects of brain injury on learning and memory, as well as LTP, and the effects of rehabilitation intervention on learning and memory after brain injury. The included 39 manuscripts were clinical, basic experimental, or review studies. DATA SYNTHESIS： Learning and memory closely correlates to LTP. The neurobiological basis of learning and memory is central nervous system plasticity, which involves neural networks, neural circuits, and synaptic connections, in particular, synaptic plasticity. LTP is considered to be an ideal model for studying synaptic plasticity, and it is also a classic model for studying neural plasticity of learning and memory. Brain injury patients clinically present with various manifestations, such as paralysis and sensory disability, which closely correlate to injured regions. In addition, learning and memory abilities decrease in brain injury patients and LTP decreases following brain injury. Brain tissue injury will lead to brain functional deficits. Hippocampal LTP is very sensitive. Difficulties in LTP induction are apparent even prior to morphological changes in brain tissue. There are no specific treatments for learning and memory functional deficits following brain injury. At present, behavioral and compensative therapies are the typical forms of rehabilitation. These results indicate that rehabilitation promotes learning and memory functional recovery in brain injury patients by speeding up LTP formation in the hippocampal CA3 region. CONCLUSION： Rehabilitation intervention increases LTP formation in the hippocampal CA3 region and recovers learning and memory functions in brain injury patients.

Corticosterone induced D-serine release deficit play an important role in long-term potentiation impairment by corticosterone in perforant path-dentate gyrus pathway

OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation(LTP)and cognitive impairment induced by stress or corticosterone.However,other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment.The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms.METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS)to induce LTP impairment.NMDA receptor antagonists and agonists were administrated by icv.RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice.Corticosterone increased the glutamate level in hippocampal tissues,neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP,while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone,suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticosterone.Further results showed that the level of D-serine and its precursor L-serine did not change.D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1(ASC-1)in the cell membrane was decreased and increasing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticosterone.CONCLUSION Taken together,this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction,which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.

Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease

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, 2015(approval No. AEEI-2015-182).

Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity

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.

Paired associative stimulation improves synaptic plasticity and functional outcomes after cerebral ischemia

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(approval No. TJ-A20151102) on July 11, 2015.