Opioids block long-term potentiation of inhibitory synapses

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.     

Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices

Long-term potentiation (LTP) of synaptic transmission in the hippocampus is a widely studied model system for understanding the cellular mechanisms of memory. In region CA1, LTP is triggered postsynaptically by Ca2(+)-dependent activation of protein kinases, but the locus of persistent modification remains controversial. Statistical analysis of synaptic variability has been proposed as a means of settling this debate, although a major obstacle has been the poor signal-to-noise ratio of conventional intracellular recordings. We have applied the whole-cell voltage clamp technique to study synaptic transmission in conventional hippocampal slices (compare refs 28-30). Here we report that robust LTP can be recorded with much improved signal resolution and biochemical access to the postsynaptic cell. Prolonged dialysis of the postsynaptic cell blocks the triggering of LTP, with no effect on expression of LTP. The improved signal resolution unmasks a large trial-to-trial variability, reflecting the probabilistic nature of transmitter release. Changes in the synaptic variability, and a decrease in the proportion of synaptic failures during LTP, suggest that transmitter release is significantly enhanced.     

Structural basis of long-term potentiation in single dendritic spines

Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.     

快速伸缩复合练习伴随血流限制的激活后增强效应研究

[目的]观察快速伸缩复合练习、血流限制,以及两者相结合对纵跳的动力学和运动学的影响.[方法]对象为运动训练专业男性大学生.随机分为对照组(C)、快速伸缩复合练习组(P)、血流限制组(B),以及快速伸缩复合练习伴随血流限制(P+B).分别在干预前、干预后测定纵跳的运动学和动力学参数.[结果]P组与P+B组在干预4 min后,有类似的显著效果;但B组不显著.[结论]单独使用血流限制不能产生激活后增强效应;快速伸缩复合练习及其与血流限制相结合,能够产生激活后增强效应.     

Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents.

Miniature excitatory synaptic currents were recorded from CA1 pyramidal cells in hippocampal slices to study the site of the persistent change in synaptic efficacy during long-term potentiation. Induction of long-term potentiation produced a large increase in the amplitude of these currents. Such a change in amplitude suggests an increase in postsynaptic transmitter sensitivity.     

Postsynaptic hyperpolarization during conditioning reversibly blocks induction of long-term potentiation

Activity-induced changes in the efficacy of synaptic transmission between neurones are central to several prominent theories of learning. In both in vivo and in vitro preparations of the hippocampus, a conditioning high-frequency stimulus delivered to afferent fibres results in a long-term potentiation of synaptic transmission at those inputs. Evidence has been provided supporting both presynaptic and postsynaptic sites as loci where critical events occur in the development of potentiation. In this study we report that long-term potentiation is reversibly blocked by intracellular injection of hyperpolarizing current in the postsynaptic cell during the conditioning high-frequency stimulus, suggesting the involvement of a voltage-dependent postsynaptic mechanism.     

Presynaptic release probability influences the locus of long-term potentiation.

The quantal hypothesis proposes that chemical synaptic transmission involves the probabilistic release of multimolecular packets of transmitter. Analysis of the resulting trial-to-trial fluctuations in postsynaptic response can provide estimates both of the number of quanta released and of the size of their postsynaptic effect. This in turn permits the quantification of the relative contributions of pre- and postsynaptic factors to the strength of a given synapse. Quantal analysis of excitatory synapses in the hippocampus has proved difficult and has led to contradictory conclusions when applied to long-term potentiation. Here we report the use of a combination of quantal analysis procedures to provide evidence that both pre- and postsynaptic changes can contribute substantially to the maintenance of long-term potentiation in the CA1 region of the hippocampus. The initial setting of the presynaptic release mechanism seems to determine their relative importance.     

不同图灵模作用的几种斑图

采用双层耦合的CIMA模型,研究了不同图灵模相互作用时斑图的选择、形成机制.结果表明:当2个子系统分别处在超临界和次临界分岔点附近时,超临界图灵模和次临界图灵模相互作用产生耦合,得到六边形和超六边斑图;当2个子系统激发的图灵模均为超临界模时,二者之间不发生耦合,每个子系统各自形成简单的条纹斑图;当2个子系统激发的图灵模均为次临界模时,2个模产生相互作用,系统最终选择完全相同的"豆角"斑图.此外,图灵模的分岔类型还改变斑图的空间对称性.     

Long-term potentiation of synaptic transmission in the hippocampus induced by a bee venom peptide

Several neurotoxins have been isolated from bee venom. One of these, the mast cell degranulating peptide (MCD), releases histamine from mast cells and on central administration produces arousal at low concentrations and convulsions at higher doses. These effects are mediated through specific high-affinity binding sites which are concentrated in cortical structures, notably the hippocampus. This structure appears to be the source of changes in the electrocorticogram that follow injections of MCD into the cerebral ventricle, and which induce a quasi-permanent hippocampal theta rhythm in the motionless rat alternating with epileptiform spike waves. We report here that brief application of MCD to the CA1 region of hippocampal slices induces long-term potentiation, that is, a long-lasting increase in the efficacy of synaptic transmission. This potentiation seems to be indistinguishable from the classical LTP produced by trains of high-frequency electrical stimulation and considered to be related in some way to memory. Using binding to synaptosomal membranes and radioimmunoassay techniques, we have also found an endogenous peptide equivalent of MCD in brain extracts. This raises the possibility that a MCD-like peptide may be important in long-term potentiation.     

Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus.

Long-term potentiation (LTP) of synaptic transmission in the hippocampus is a widely studied model of memory processes. In the CA1 region, LTP is triggered by the entry of Ca2+ through N-methyl-D-aspartate (NMDA) receptor channels and maintained by the activation of Ca2(+)-sensitive intracellular messengers. We now report that in CA1, a transient block by tetraethylammonium of IC, IM and the delayed rectifier (IK) produces a Ca2(+)-dependent NMDA-independent form of LTP. Our results suggest that this new form of LTP (referred as to LTPK) is induced by a transient enhanced release of glutamate which generates a depolarization by way of the non-NMDA receptors and the consequent activation of voltage-dependent Ca2+ channels.     

Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex

In the hippocampus and neocortex, high-frequency (tetanic) stimulation of an afferent pathway leads to long-term potentiation (LTP) of synaptic transmission. In the hippocampus it has recently been shown that long-term depression (LTD) of excitatory transmission can also be induced by certain combinations of synaptic activation. In most hippocampal and all neocortical pathways studied so far, the induction of LTP requires the activation of N-methyl-D-aspartate (NMDA) receptor-gated conductances. Here we report that LTD can occur in neurons of slices of the rat visual cortex and that the same tetanic stimulation can induce either LTP or LTD depending on the level of depolarization of the postsynaptic neuron. By applying intracellular current injections or pharmacological disinhibition to modify the depolarizing response of the postsynaptic neuron to tetanic stimulation, we show that the mechanisms of induction of LTD and LTP are both postsynaptic. LTD is obtained if postsynaptic depolarization exceeds a critical level but remains below a threshold related to NMDA receptor-gated conductances, whereas LTP is induced if this second threshold is reached.     

Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5

Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.     

Associative long-term depression in the hippocampus induced by hebbian covariance

A brief, high-frequency activation of excitatory synapses in the hippocampus produces a long-lasting increase in synaptic strengths called long-term potentiation (LTP). A test input, which by itself does not have a long-lasting effect on synaptic strengths, can be potentiated through association when it is activated at the same time as a separate conditioning input. Neural network modelling studies have also predicted that synaptic strengths should be weakened when test and conditioning inputs are anti-correlated. Evidence for such heterosynaptic depression in the hippocampus has been found for inputs that are inactive or weakly active during the stimulation of a conditioning input, but this depression does not depend on any pattern of test input activity and does not seem to last as long as LTP. We report here an associative long-term depression (LTD) in field CA1 that is produced when a low-frequency test input is negatively correlated in time with a high-frequency conditioning input. LTD of synaptic strength is also produced by activating presynaptic terminals while a postsynaptic neuron is hyperpolarized. This confirms theoretical predictions that the mechanism for associative LTD is homosynaptic and follows a hebbian covariance rule.     

Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo

Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.     

不同产地短管兔耳草脂溶性化学成分的GC-MS分析

采用毛细管色谱-质谱联用技术对青海省不同产地短管兔耳草脂溶性化学成分进行了研究,共分离鉴定出40种不同化合物,有11种成分为3个产地所共有.比较发现不同产地短管兔耳草脂溶性化学成分及相对含量存在差异,为该种药材品种及产地的鉴别和品质比较提供了一定依据.     

Two homologous protein components of hepatic gap junctions

Gap junctions consist of closely packed pairs of transmembrane channels, the connexons, through which materials of low relative molecular mass diffuse from the cell to neighbouring cells. In liver, connexons consist of six protein subunits which, until now, were believed to be identical. However, besides the major polypeptide of relative molecular mass (Mr) 28,000 (and see refs 4 and 6), a component of Mr 21,000 (21K) has been repeatedly observed in liver. The amino-terminal sequence (18 residues) of this less abundant protein shows that it is related to, but distinct from, the Mr 28K protein. Immuno-staining and immuno-precipitation show both proteins to be in the same gap junctional plaques. Thus, it seems that hepatic gap junction channels (and by extension possibly others) are composed of two (or more) homologous proteins.