Blocking postsynaptic density-93 binding to C-X3-C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke

We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.

Effect of Panaxtriol Saponins on synaptophysin and postsynaptic density-95 expression at different periods of cerebral infarction

BACKGROUND： The change in expression of synaptophysin （Syp） and postsynaptic density-95 （PSD-95） alters after cerebral infarction, and the plasticity of synapses contributes greatly to nerve function recovery. Chinese medicinal substances may play an important role in the expression of Syp and PSD-95. OBJECTIVE： To observe the effect of Panaxtriol Saponins （PTS）, an active component in Sanqi tongshu capsules, on the expression of Syp and PSD-95 after cerebral infarction at different time points in rats, so as to examine the cerebral function remodeling mechanism. DESIGN, TIME AND SETTING： A randomized and controlled observation which was performed in Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine from January to March, 2007. MATERIALS： Twenty-six healthy male Sprague Dawley rats were used to establish middle cerebral artery occlusion based on the Longa method. Sanqi tongshu capsules （containing 100 mg PTS per tablet） were provided by the Chengdu Huashen Group and nimodipine tablets （30 mg） by Tianjin Zhongyang Pharmaceutical Co., Ltd. METHODS： Twenty-six rats were randomly divided into an operation group （n = 21 ） and a control group （n = 5）. The operation group underwent the EZ Longa procedure to make the middle cerebral artery occlusion model. After surgery rats were randomly divided into a model group, a PTS group and a nimodipine group, with seven rats in each group. Rats were intragastrically administrated with saline （2 mL/d） in the model group, with Sanqi tongshu capsule （5.4 mg/100 g/d） in the PTS group, and with nimodipine （1.73 mg/100 g/d） in the nimodipine group. Rats in the control group did not undergo model establishment and drug administration. MAIN OUTCOME MEASURES： The expressions of Syp and PSD-95 were measured by immunohistochemical and image analysis at days 3, 7 and 28 after the operation. RESULTS： The expression of Syp and PSD-95 in the operation group was significantly lower than in the control group at days 3, 7, 28 postoperatively （P 〈 0.05）. The expression of Syp and PSD-95 in the PTS group and nimodipine group was significantly higher than in the model group at day 28 postoperatively （P 〈 0.05-0.01）. Additionally, after PTS and nimodipine treatment at different intervals, the expression of Syp and PSD-95 at day 28 postoperatively was significantly higher than those at days 3 and 7 postoperatively, respectively （P 〈 0.01）. CONCLUSION： PTS can promote the expression of Syp and PSD-95, i.e. the remodeling process of synapses, after cerebral infarction at different time points in rats, which contributes to cerebral function remodeling.

Acute pathological changes of facial nucleus and expressions of postsynaptic density protein-95 following facial nerve injury of varying severity A semi-quantitative analysis

BACKGROUND： Previous studies have demonstrated that postsynaptic density protein-95 （PSD-95） is widely distributed in the central nervous system and is related to the development of the CNS and sensory signal transmission as well as acute or chronic nerve cell death following ischemic brain injury. OBJECTIVE： To semi-quantitatively determine the pathological changes of apoptotic facial neurons and the expression of PSD-95 in the facial nucleus following facial nerve injury of varying extents using immunohistochemical staining methods. DESIGN, TIME AND SETTING： Randomized, controlled animal experiments were performed in the Ultrasonic Institute of the Second Affiliated Hospital of Chongqing University of Medical Sciences from September to December 2007. MATERIALS： Sixty-five healthy, adult, Sprague-Dawley （SD） rats, both male and female, were used for this study. Rabbit anti-rat PSD-95 polyclonal antibody was purchased from Beijing Biosynthesis Biotechnology Co., Ltd. METHODS： SD rats were randomly assigned into a control group with five rats and three injured groups with 20 rats per group. Exposure, clamp and cut for bilateral facial nerve trunks were performed in the rats of the injury groups, and no injury was inflicted on the rats of the control group. MAIN OUTCOME MEASURES; The brainstems of all the rats were excised on days 1, 3, 7, and 14 post injury, and then the facial nuclei were stained with hematoxylin-eosin to observe any pathological changes due to apoptosis in facial neurons. PSD-95 expression in facial nuclei was detected by immunohistochemistry and the number of PSD-95 positive cells was counted under a light microscope. RESULTS： The expression of PSD-95 in the facial nucleus and morphology of the facial neuron within the exposure group had no obvious changes at various points in time tested （P 〉 0.05）. However, the expressions of PSD-95 in the facial nucleus of the clamp group and cut group increased on day 1 post injury （P 〈 0.05）, and showed further increase on day 7 post injury （P 〈 0.01 ）. This did not decrease until day 14 post injury. Facial neuron apoptosis was detected on day 3 post injury and this was even more obvious on day 7 and was maintained to day 14 post injury. The number of cells expressing PSD-95 and displaying severe degrees of facial neuron apoptosis were as follows： cut group 〉 clamp group 〉 exposure group. CONCLUSION： The apoptotic extent of facial neurons and the expression of PSD-95 in apoptotic facial neurons increased with the degree of aggravation of injured severity of facial nerve.

Effect of sodium ferulate on activation of postsynaptic density-95 after transient facol cerebral ischemia

It was confirmed that sodium ferulate (SF) could significantly improve neurologic function deficit, reduce cerebral infarct volume at 24 h after reperfusion, and weakened postsynaptic density-95 (PSD-95) activation in ische-mic area reacting to ischemia after transient middle cerebral artery occlusion ( MCAO) by Western immunoblot analy-

Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory

Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability.Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and memory.Here,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory deficits.To test this,we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre.We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in mice.These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Propofol enhances the field excitatory postsynaptic potentials in CA1 hippocampal slices of young and aged mice

Background Increasing age was shown to decrease the requirements for propfol.However,the mechanisms of ageing-induced potentiation of anesthetic actions have not been clearly explored.The aim of this study is to compare the effects of propofol on the field excitatory postsynaptic potentials （fEPSPs） in hippocampal slices of young and aging mice.Methods Brain slices were prepared from C57BL6 male young （2 months） and aging （＞12 months） mice.The dendritic field excitatory postsynaptic potential was recorded from the CA1 stratum radiatum using patch clamp electrophysiological methods.A bipolar concentric stimulating electrode was placed along the Schaffer collateral for othodromic stimulation.The effects of clinically-relevant concentrations of propofol were studied in the young and ageing mouse tissues.Results Propofol application increased the orthodromically evoked fEPSP produced in slices taken from young and older animals.A striking feature in the I/O relationship was the decreased enhancement of the fEPSPs by propofol in slices from older mice.A clinically relevant concentration of propofol,10 μmol/L,showed more significant enhancement in amplitude and area under the curve （AUC） of fEPSP in young compared to tissues from older mice （amplitude：young （24.9±3.4）％,old （4.6±1.6）％; AUC young （30.6±5.4）％,old （2.1±1.7）％）.There was no statistically significant difference between the paired-pulse facilitation （PPF） ratios calculated for the responses obtained in tissues from young mice.In slices from older mice,in the presence of 10 μmol/L propofol,PPF was decreased and returned to baseline after washout （baseline 1.21±0.01,propofol：1.16±0.01）.Bicuculline （15 μmol/L） blocked the enhancement of propofol on fEPSP in tissues from young and old mice.Conclusion The fEPSP of slices from aging mice demonstrates diminished sensitivity to the enhancing actions of propofol.

Neuroprotective effect of sodium ferulate on transient focal cerebral ischemia by weakening activation of postsynaptic density-95 in rats

Objective： To investigate the effects of sodium ferulate （SF）, an intravenous drug made from traditional Chinese herbs, on activation of postsynaptic density-95 （PSD-95） and neuroprotection after transient cerebral artery occlusion in rats. Methods： Forty-six male Sprague-Dawley rats were randomized into 2 groups （ n = 23 in each group） ： the control group and the SF group. After anesthesia, the middle cerebral artery occlusion （MCAO） was conducted with the intraluminal filament technique. The neurological deficit was assessed with the method devised by Bederson et al.^ 8 The 2, 3, 4-triphenyltetrazolium chloride staining was used to assess the infarct volume. We adopted a modified six-point scale to conduct neurobehavioral evaluation. Immediately the activation of postsynaptic density-95 （ PSD- 95 ） was studied with Western blot analysis system in the cortex and striatum of rat brain. Results ： The neurologic deficit score of the SF group decreased substantially compared with that of the control group （ P 〈0.05）. The infarct volume of the control group （168.1 mm^3 ± 42.2 mm^3） was significantly larger than that of the SF group （61.5 mm^3 ± 28.7 mm^3 ） at 24 hours after reperfusion （P 〈 0.01 ）. And the rats showed some neurological deficit. The activity of PSD-95 in the SF group at most timepoints was less than that in the control group. No upregulation of PSD-95 protein could be detected in the contralateral cortex. Conclusions ： Sodium ferulate can induce a neuroproteetive effect against the transient focal cerebral isehemie injury and weaken the activation of PSD-95 in isehemie area after MCAO.

Non-cholinergic late slow excitatory postsynaptic potential, 5-hydroxytryptamine and substance P

It has been recognized that substance P (SP) and 5-hydroxytryptamine (5-HT) maybe the transmitters mediating non-cholinergic late slow excitatory postsynaptic potential(LS-EPSP) in the neurons of guinea pig inferior mesenteric ganglion (IMG). The

Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro

Objective Postsynaptic density protein 95 （PSD-95） plays important roles in the regulation of glutamate signaling, such as that of N-methyl-D-aspartate receptors （NMDARs）. In this study, the functional roles of PSD-95 in tyrosine phosphorylafion of NMDAR subunit 2A （NR2A） and in apoptosis-like cell death induced by oxygen-glucose de- privation （OGD） in cultured rat cortical neurons were investigated. Methods We used immunoprecipitation and immuno- blotting to detect PSD-95 protein level, tyrosine phosphorylation level of NR2A, and the interaction between PSD-95 and NR2A or Src. Apoptosis-like cells were observed by 4,6-diamidino-2-phenylindole staining. Results Tyrosine phospho- rylation of NR2A and apoptosis-like cell death were increased after recovery following 60-min OGD. The increases were attenuated by pretreatment with antisense oligonucleotides against PSD-95 before OGD, but not by missense oligonucle- otides or vehicle. PSD-95 antisense oligonucleotides also inhibited the increased interaction between PSD-95 and NR2A or Src, while NR2A expression did not change under this condition. Conclusion PSD-95 may be involved in regulating NR2A tyrosine phosphorylation by Src kinase. Inhibition of PSD-95 expression can be neuroprotective against apoptosis- like cell death after recovery from OGD.

Postsynaptic Excitation of Prefrontal Cortical Pyramidal Neurons by Hypocretins/Orexins

Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,

Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function

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.

突触后致密物与癫痫苔藓纤维出芽

突触后致密物是化学性突触后膜内侧的特化结构,为神经信息传递的重要结构基础,参与突触后信号转导的调节和整合,在学习、记忆和突触可塑性等生理过程中有重要作用。近年来发现,癫痫发作伴有突触后致密物成分的改变,可能参与了癫痫的病理生理过程。

An enriched environment promotes synaptic plasticity and cognitive recovery after permanent middle cerebral artery occlusion in mice

Cerebral ischemia activates an endogenous repair program that induces plastic changes in neurons. In this study, we investigated the effects of environmental enrichment on spatial learning and memory as well as on synaptic remodeling in a mouse model of chronic cerebral ischemia, produced by subjecting adult male C57 BL/6 mice to permanent left middle cerebral artery occlusion. Three days postoperatively, mice were randomly assigned to the environmental enrichment and standard housing groups. Mice in the standard housing group were housed and fed a standard diet. Mice in the environmental enrichment group were housed in a cage with various toys and fed a standard diet. Then, 28 days postoperatively, spatial learning and memory were tested using the Morris water maze. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 in the hippocampus were analyzed by western blot assay. The number of synapses was evaluated by electron microscopy. In the water maze test, mice in the environmental enrichment group had a shorter escape latency, traveled markedly longer distances, spent more time in the correct quadrant(northeast zone), and had a higher frequency of crossings compared with the standard housing group. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 were substantially upregulated in the hippocampus in the environmental enrichment group compared with the standard housing group. Furthermore, electron microscopy revealed that environmental enrichment increased the number of synapses in the hippocampal CA1 region. Collectively, these findings suggest that environmental enrichment ameliorates the spatial learning and memory impairment induced by permanent middle cerebral artery occlusion. Environmental enrichment in mice with cerebral ischemia likely promotes cognitive recovery by inducing plastic changes in synapses.

High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1–42-induced Alzheimer＇s disease

Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42（Aβ_（1–42））into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui（GV20;15°obliquely to a depth of 2mm）and Shenshu（BL23;perpendicularly to 4–6 mm depth）,once a day for 20 minutes（each）,for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β（GSK-3β）,p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_（1–40） in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_（1–40）.pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency（50 Hz）electroacupuncture was more effective than low（2 Hz）or medium-frequency（30 Hz）electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_（1–42）-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.

Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease

Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.

Protective effects of Dendrobium nobile Lindl. alkaloids on amyloid beta(25–35)-induced neuronal injury

Dendrobium nobile Lindl.alkaloids（DNLA）,the active ingredients of a traditional Chinese medicine Dendrobium,have been shown to have anti-oxidative effects,anti-inflammatory action,and protective effect on neurons against oxygen-glucose deprivation.However,it is not clear whether DNLA reduces amyloid-beta（Aβ）-induced neuronal injury.In this study,cortical neurons were treated with DNLA at different concentrations（0.025,0.25,and 2.5 mg/L）for 24 hours,followed by administration of Aβ（25-35）（10μM）.Aβ（25-35） treatments increased cell injury as determined by the leakage of lactate dehydrogenase,which was accompanied by chromatin condensation and mitochondrial tumefaction.The damage caused by Aβ（25-35） on these cellular properties was markedly attenuated when cells were pretreated with DNLA.Treatment with Aβ（25-35）down-regulated the expressions of postsynaptic density-95 mRNA and decreased the protein expression of synaptophysin and postsynaptic density-95,all changes were significantly reduced by pretreatment of cells with DNLA.These findings suggest that DNLA reduces the cytotoxicity induced by Aβ（25-35） in rat primary cultured neurons.The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated,at least in part,through the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95.

Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer's disease mice

Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer＇s disease. To test this hypothe- sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 （APP/PS1） mice using the agonist clenbuterol （intraperitoneal injection, 2 mg/kg）. We found that β2-adrenoceptor ac- tivation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines, lhese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS 1 mice.

ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

The selective hyperpolarization-activated cyclic nucleotide-gated（HCN） channel blocker 4-（N-ethyl-N-phenylamino）-1,2-dimethyl-6-（methylamino） pyrimidinium chloride（ZD7288） blocks the induction of long-term potentiation in the perforant path-CA3 region in rat hippocampus in vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path-CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hippocampal neurons using high performance liquid chromatography, and determined intracellular Ca2＋ concentration（[Ca2＋]i） using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspecific HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Furthermore, ZD7288 attenuated glutamate-induced rises in [Ca2＋]i in a concentration-dependent manner and reversed 8-Br-c AMP-mediated facilitation of these glutamate-induced [Ca2＋]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both glutamate release and resultant [Ca2＋]i increases in rat hippocampal neurons.

Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1

In this study, we investigated the effects of mobile phone radiation on spatial learning, reference memory, and morphology in related brain regions. After the near-field radiation （0.52 1.08 W/kg） was delivered to 8-week-old Wistar rats 2 hours per day for 1 month, behavioral changes were examined using the Morris water maze. Compared with the sham-irradiated rats, the irradiated rats exhibited impaired performance. Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus. Using the physical dissector technique, the number of pyramidal neurons, the synaptic profiles, and the length of postsynaptic densities in the CA1 region were quantified stereologically. The morphological changes included mitochondrial degenerations, fewer synapses, and shorter postsynaptic densities in the radiated rats. These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region.