Postsynaptic long-term potentiation follows coupling of dendritic glutamate application and synaptic activation

Summary Dendritic depolarization, which seems to be involved in the induction of long-term potentiation (LTP), was elicited by localized glutamate application. When paired to low frequency synaptic activation in the same area, the subsequent changes had features in common with LTP, expressed as an increased probability of firing and shorter spike latency. The EPSP was not significantly increased.     

The role of endosomal-recycling in long-term potentiation

Long-term potentiation (LTP) defines persistent increases in neurotransmission strength at synapses that are triggered by specific patterns of neuronal activity. LTP, the most widely accepted molecular model for learning, is best characterised at glutamatergic synapses on dendritic spines. In this context, LTP involves increases in dendritic spine size and the insertion of glutamate receptors into the post-synaptic spine membrane, which together boost post-synaptic responsiveness to neurotransmitters. In dendrites, the material required for LTP is sourced from an organelle termed the endosomal-recycling compartment (ERC), which is localised to the base of dendritic spines. When LTP is induced, material derived from the recycling compartment, which contains α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptors (AMPARs), is mobilised into dendritic spines feeding the increased need for receptors and membrane at the spine neck and head. In this review, we discuss the importance of endosomal-recycling and the role of key proteins which control these processes in the context of LTP.     

CDK5 downregulation enhances synaptic plasticity

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity—such as long-term potentiation (LTP)—have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca²⁺ signaling and BDNF/CREB activation.     

Stimulation parameters determine role of GABAB receptors in long-term potentiation

Blockade of GABA_B receptors was reported to improve cognitive performance in mammals. The physiological basis of this effect is poorly understood. We investigated the effect of the GABA_B receptor antagonist CGP 35348 on long-term potentiation (LTP) in the CA1 area of the hippocampus in vitro and in vivo. In vitro the effect of CGP 35348 on LTP, induced either by two non-primed tetanic stimulations or by two primed bursts of stimuli, was investigated. In the presence of 1 mM CGP 35348 LTP was significantly facilitated following two non-primed tetanic trains, but was impaired following two primed burst stimulations. In vivo LTP was induced by applying non-primed trains of stimuli of increasing duration to the Schaffer collateral/commissural fibers. The potentiation of the population spike recorded in CA1 was significantly facilitated by CGP 35348 (100 mg/kg i.v.). In conclusion these findings demonstrate that the GABA_B antagonist CGP 35348 facilitates LTP in vitro and in vivo if induced by non-primed tetanic stimulation. In vitro, the mode of stimulation determines the effect of the GABA_B antagonist on LTP.     

Interaction of lipid transfer protein with plasma lipoproteins and cell membranes

Summary The hydrophobic lipid components of lipoproteins, cholesteryl ester and triglyceride, are transferred between all lipoproteins by a specific plasma glycoprotein, termed lipid transfer protein (LTP). LTP facilitates lipid transfer by an exchange process in which cholesteryl ester and triglyceride compete for transfer. Thus, LTP promotes remodeling of the lipoprotein structure, and plays an important role in the intravascular metabolism of these particles and in the lipoprotein-dependent pathways of cholesterol clearance from cells. The properties of LTP, its mechanisms of action, its roles in lipoprotein metabolism, and its modes of regulation are reviewed along with recent data that suggest a possible role for this protein in directly modifying cellular lipid composition.     

Furin promotes dendritic morphogenesis and learning and memory in transgenic mice

Furin is a proprotein convertase implicated in a variety of pathological processes including neurodegenerative diseases. However, the role of furin in neuronal plasticity and learning and memory remains to be elucidated. Here, we report that in brain-specific furin transgenic (Furin-Tg) mice, the dendritic spine density and proliferation of neural progenitor cells were significantly increased. These mice exhibited enhanced long-term potentiation (LTP) and spatial learning and memory performance, without alterations of miniature excitatory/inhibitory postsynaptic currents. In the cortex and hippocampus of Furin-Tg mice, the ratio of mature brain-derived neurotrophic factor (mBDNF) to pro-BDNF, and the activities of extracellular signal-related kinase (ERK) and cAMP response element-binding protein (CREB) were significantly elevated. We also found that hippocampal knockdown of CREB diminished the facilitation of LTP and cognitive function in Furin-Tg mice. Together, our results demonstrate that furin enhances dendritic morphogenesis and learning and memory in transgenic mice, which may be associated with BDNF–ERK–CREB signaling pathway.     

HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path

Neuronal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate spontaneous activity, resting membrane potential, input resistance, afterpotential, rebound activity, and dendritic integration. To evaluate the role of HCN2 for hippocampal synaptic plasticity, we recorded long-term potentiation (LTP) in the direct perforant path (PP) to CA1 pyramidal cells. LTP was enhanced in mice carrying a global deletion of the channel (HCN2^−/−) but not in a pyramidal neuron-restricted knockout. This precludes an influence of HCN2 located in postsynaptic pyramidal neurons. Additionally, the selective HCN blocker zatebradine reduced the activity of oriens-lacunosum moleculare interneurons in wild-type but not HCN2^−/− mice and decreased the frequency of spontaneous inhibitory currents in postsynaptic CA1 pyramidal cells. Finally, we found amplified LTP in the PP of mice carrying an interneuron-specific deletion of HCN2. We conclude that HCN2 channels in inhibitory interneurons modulate synaptic plasticity in the PP by facilitating the GABAergic output onto pyramidal neurons.     

Modification of glutamate receptors by phospholipase A2: its role in adaptive neural plasticity

Long-term potentiation (LTP) and long-term depression (LTD) are two electrophysiological models that have been studied extensively in recent years as they may represent basic mechanisms in many neuronal networks to store certain types of information. In several brain regions, it has been shown that these two forms of synaptic plasticity require sufficient dendritic depolarization, with the amplitude of the calcium signal being crucial for the generation of either LTP or LTD. The rise in calcium concentration mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent enzymatic processes that could convert the induction signal into long-lasting changes in synaptic structure; protein kinases and phosphatases have so far been considered predominantly with regard to LTP and LTD formation. According to several lines of experimental evidence, changes in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. Moreover, it has become apparent recently that activation of the calcium-dependent enzyme phospholipase A2 (PLA2) could be part of the molecular mechanisms involved in alterations of AMPA receptor properties during long-term changes in synaptic operation. In the present review, we will first describe the results that indicate a critical role of the phospholipases in regulating synaptic function. Next, sections will be devoted to the effects of PLA2 and phospholipids on the binding properties of glutamate receptors, and a revised biochemical model will be presented as an attempt to integrate the PLA2 enzyme into the mechanisms ( in particular kinases and phosphatases) that participate in adaptive neural plasticity. Finally, we will review data relevant to the issue of selective changes in AMPA binding after environmental enrichment and LTP.     

Lipid transfer in plants

Summary Plant cells contain cytosolic proteins, called lipid transfer proteins (LTP), which are able to facilitate in vitro intermembrane transfer of phospholipids. Proteins of this kind from three plants, purified to homogeneity, have several properties in common: molecular mass around 9 kDa, high isoelectric point, lack of specificity for phospholipids, and binding ability for fatty acids. The comparison of their amino acid sequences revealed striking homologies and conserved domains which are probably involved in their function as LTPs. These proteins could play a major role in membrane biogenesis by conveying phospholipids from their site of biosynthesis to membranes unable to form these lipids. Immunochemical methods were used to establish an in vivo correlation between membrane biogenesis and the level of LTP or the amount of LTP synthesized in vitro from mRNAs. The recent isolation of a full-length cDNA allows novel approaches to studying the participation of LTPs in the biogenesis of plant cell membranes.     

Sex difference in liver tryptophan pyrrolase activity of starved rats

Zusammenfassung Die Tryptophanpyrrolase (LTP) ausgewachsener weiblicher Ratten nimmt während 4-stündiger Hungerperiode von 1,06µM Kynurenin auf 2,26µM/g/h zu. Sie erreicht nach 24 h wieder Normalwerte, um dann während einer 8tägigen Hungerperiode auf 5,75µM/g/h anzusteigen. Die LTP männlicher Ratten zeigt nur unbedeutenden Anstieg während gleicher Hungerperioden.     

Developmental nicotine exposure induced alterations in behavior and glutamate receptor function in hippocampus

In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral, neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission, and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845) GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes.     

早期母子隔离应激对大鼠学习记忆能力的影响

目的探讨早期母子隔离应激对幼鼠学习记忆能力的影响。方法30只SD新生大鼠用于实验,实验随机分成3组,正常对照纽、母子隔离15分钟纽、母子隔离3小时纽。在生后40天,三组大鼠进行Morris水迷宫及记录海马脑片长时程增强电位（LTP）实验。结果Morris水迷宫测试,与正常组比较母子隔离3h组大鼠寻找平台需要的潜伏期延长（P〈0．05）,而母子隔离15分钟组大鼠寻找平台需要的潜伏期与正常组比较则无明显变化（P〉0．05）;海马脑片长时程增强电位提示：正常对照组条件刺激（CS）前后fEPSP斜率变化率为：64．7±22．9％;母子隔离3h组为：35．3±14．2％,低于正常组（P〈0．01）;母子隔离15min组为：66．3±29．7％,与正常组比较无显著性意义（P〉0．05）。结论幼鼠生后早期过度的应激导致大鼠的学习记忆能力减弱。     

Insulin can induce the expression of a memory-related synaptic protein through facilitating AMPA receptor endocytosis in rat cortical neurons

Learning and memory depend on long-term synaptic plasticity including long-term potentiation (LTP) and depression (LTD). Activity-regulated cytoskeleton-associated protein (Arc) plays versatile roles in synaptic plasticity mainly through inducing F-actin formation, underlying consolidation of LTP, and promoting AMPA receptor (AMPAR) endocytosis, underlying LTD. Insulin can also induce LTD by facilitating the internalization of AMPARs. In neuroblastoma cells, insulin induced a dramatic increase in Arc mRNA and Arc protein levels, which may underlie the memory-enhancing action of insulin. Thus, a hypothesis was made that, in response to insulin, increased AMPAR endocytosis leads to enhanced Arc expression, and vice versa. Primary cultures of neonatal Sprague–Dawley rat cortical neurons were used. Using Western-blot analysis and immunofluorescent staining, our results reveal that inhibiting AMPAR-mediated responses with AMPAR antagonists significantly enhanced whereas blocking AMPAR endocytosis with various reagents significantly prevented insulin (200 nM, 2 h)-induced Arc expression. Furthermore, via surface biotinylation assay, we demonstrate that acute blockade of new Arc synthesis after insulin stimulation using Arc antisense oligodeoxynucleotide prevented insulin-stimulated AMPAR endocytosis. These findings suggest for the first time that an interaction exists between insulin-stimulated AMPAR endocytosis and insulin-induced Arc expression.     

Formation of lipoperoxide in the retina of rabbit exposed to high concentration of oxygen.

When rabbit was exposed to high concentrations of oxygen, lipoperoxide in the retina was increased at 12 h of the exposure, after which period amplitude of electro-retinogram decreased. The degeneration was observed in the visual cell layer of the retina of the exposed animal.The exposure increased lipoperoxide in isolated retina. These data show the intervention of lipoperoxide in retinal degeneration by exposure to high concentration of oxygen.     

Lecithin-cholesterol acyltransferase activity in carbohydrate-induced hypertriglyceridemia in mice. An immunofluorescent method for identification of isolated thyrotropic cells

Summary Feeding to mice of both basal as well as high sucrose diet led to increased levels of plasma triglycerides, which was associated with increased lecithin-cholesterol acyltransferase activity. Although males had significantly higher LCAT activity than females in all the dietary groups, sex difference in the plasma triglycerides was observed in high sucrose group only. Increase in plasma triglycerides in experimental groups was associated with an increase in LCAT activity.     

Human platelet 5-hydroxytryptamine receptors: binding of [3H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration

Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently 125I/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor responsible for 5-HT-induced shape change and aggregation. In a group of patients receiving phenothiazines or thioxanthenes, the Bmax of LSD binding was increased. The mean binding affinity was decreased possibly due to a persistence of neuroleptic in the platelet membrane preparation. Analysis showed that this was not the reason why the mean binding capacity was increased. The results show that chronic phenothiazine and thioxanthene delta treatment 'up-regulates' platelet 5-HT2 binding sites and that this may be accompanied by increased sensitivity to platelet aggregation by 5-HT. In normal subjects desipramine treatment increased the Bmax of platelet LSD binding and this was accompanied by an increased prolactin response to tryptophan which is thought to be mediated by central 5-HT function.     

Agmatine iminohydrolase activity during development and germination of groundnut seeds

Summary During the development of groundnut seeds agmatine iminohydrolase activity increased in the cotyledons but remained constant in the embryo. In seeds stored for 1 year, decreased activity of the enzyme was found in both cotyledons and embryo. During germination, the enzyme activity increased in the cotyledons, but in the embryo it increased up to day 3 and then decreased to the initial level.Acknowledgments. This work was supported by grants from the University Grants Commission under the DSA programme. We thank Dr S.K. Srivastava for his helpful suggestions and giving us access to his facilities.     

Lecithin-cholesterol acyltransferase activity in carbohydrate-induced hypertriglyceridemia in mice

Feeding to mice of both basal as well as high sucrose diet led to increased levels of plasma triglycerides, which was associated with increased lecithin-cholesterol acyltransferase activity. Although males had significantly higher LCAT activity than females in all the dietary groups, sex difference in the plasma triglycerides was observed in high sucrose group only. Increase in plasma triglycerides in experimental groups was associated with an increase in LCAT activity.     

Formation of lipoperoxide in the retina of rabbit exposed to high concentration of oxygen

Summary When rabbit was exposed to high concentration of oxygen, lipoperoxide in the retina was increased at 12 h of the exposure, after which period amplitude of electro-retinogram decreased. The degeneration was observed in the visual cell layer of the retina of the exposed animal. The exposure increased lipoperoxide in isolated retina. These data show the intervention of lipoperoxide in retinal degeneration induced by exposure to high concentration of oxygen.     

Effect of taurine administration on liver lipids in guinea pig

The oral administration of 0.4% taurine in drinking water for 14 consecutive days showed the following hepatic effects in male guinea pig. The percentage of tauro-conjugated biliary bile acids was increased from 17.2-54.2%; the ratio liver weight/body weight was increased, and fatty change was induced. Liver triglyceride concentration was accordingly increased; diglyceride and phosphatidylcholine concentrations were reduced by the treatment, while phosphatidylethanolamine level was not affected. These changes suggest an adverse effect of taurine administration on phosphatidylcholine hepatic synthesis.