Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation

The anterior cingulate cortex (ACC) is critical for brain functions including learning, memory, fear and pain. Long-term synaptic potentiation (LTP), a cellular model for learning and memory, has been reported in the ACC neurons. Unlike LTP in the hippocampus and amygdala, two key structures for memory and fear, little is known about the synaptic mechanism for the expression of LTP in the ACC. Here we use whole-cell patch clamp recordings to demonstrate that cingulate LTP requires the functional recruitment of GluR1 AMPA receptors; and such events are rapid and completed within 5-10 min after LTP induction. Our results demonstrate that the GluR1 subunit is essential for synaptic plasticity in the ACC and may play critical roles under physiological and pathological conditions.     

寡聚体Aβ1-42对大鼠海马突触可塑性的慢性影响

突触传递的长时程抑制(long-term depression,LTD)和长时程增强(longterm-potentiation,LTP)是突触可塑性的两种重要形式,并且与学习记忆密切相关.本文探讨Sprague-Dawley(SD)大鼠在海马齿状回区(dentate gyrus,DG)注射36 h孵育形成的寡聚体Aβ...     

Viagra for your synapses: Enhancement of hippocampal long-term potentiation by activation of beta-adrenergic receptors

Beta-adrenergic receptors (β-ARs) critically modulate long-lasting synaptic plasticity and long-term memory storage in the mammalian brain. Synaptic plasticity is widely believed to mediate memory storage at the cellular level. Long-term potentiation (LTP) is one type of synaptic plasticity that has been linked to memory storage. Activation of β-ARs can enhance LTP and facilitate long-term memory storage. Interestingly, many of the molecular signaling pathways that are critical for β-adrenergic modulation of LTP mirror those required for the persistence of memory. In this article, we review the roles of signaling cascades and translation regulation in enabling β-ARs to control expression of long-lasting LTP in the rodent hippocampus. These include the cyclic-AMP/protein kinase-A (cAMP–PKA) and extracellular signal-regulated protein kinase cascades, two key pathways known to link transmitter receptors with translation regulation. Future research directions are discussed, with emphasis on defining the roles of signaling complexes (e.g. PSD-95) and glutamatergic receptors in controlling the efficacy of β-AR modulation of LTP.     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.     

A synaptic model for pain: long-term potentiation in the anterior cingulate cortex

Investigation of molecular and cellular mechanisms of synaptic plasticity is the major focus of many neuroscientists. There are two major reasons for searching new genes and molecules contributing to central plasticity: first, it provides basic neural mechanism for learning and memory, a key function of the brain; second, it provides new targets for treating brain-related disease. Long-term potentiation (LTP), mostly intensely studies in the hippocampus and amygdala, is proposed to be a cellular model for learning and memory. Although it remains difficult to understand the roles of LTP in hippocampus-related memory, a role of LTP in fear, a simplified form of memory, has been established. Here, I will review recent cellular studies of LTP in the anterior cingulate cortex (ACC) and then compare studies in vivo and in vitro LTP by genetic/ pharmacological approaches. I propose that ACC LTP may serve as a cellular model for studying central sensitization that related to chronic pain, as well as pain-related cognitive emotional disorders. Understanding signaling pathways related to ACC LTP may help us to identify novel drug target for various mental disorders.     

Effects of hyperdynamic fields on input-output relationships and long-term potentiation in the rat hippocampus

The effects of a 2G force environment on synaptic plasticity were examined in the rat hippocampus. Field potentials from neurons in the CA1 pyramidal cell layer were evoked by stimulation of the afferent Schaffer collateral/commissural fibers in an in vitro slice preparation. Input-output (I-O) relationships of the circuit were determined before and after tetanizing stimuli given to induce long term potentiation (LTP), a form of neural plasticity. I-O curves from animals exposed to 2G via centrifugation for either 2 or 14 days were not different from those obtained in control (1G) animals. Similarly, induction of LTP was equivalent in all groups, showing increases in maximum amplitude, slope and midpoint response of the fitted Boltzmann functions compared to un-tetanized controls. Comparison of slices from dorsal and ventral hippocampus showed the location of the slice had no effect of LTP expression. We conclude that, in contrast to other reports of functional changes in the central nervous system under altered force environments, cellular mechanisms of synaptic plasticity, which may underlie learning and memory, are preserved in the hippocampus.     

Glutamate receptors and signal transduction in learning and memory

The plasticity of the central nervous system helps form the basis for the neurobiology of learning and memory. Long-term potentiation (LTP) is the main form of synaptic plasticity, reflecting the activity level of the synaptic information storage process, and provides a good model to study the underlying mechanisms of learning and memory. The glutamate receptor-mediated signal pathway plays a key role in the induction and maintenance of LTP, and hence the regulation of learning and memory. The progress in the understanding of the glutamate receptors and related signal transduction systems in learning and memory research are reviewed in this article.     

Long-term potentiation and the ageing brain

Ageing is associated with learning and memory impairments. Data are reviewed that suggest that age-related impairments of hippocampal-dependent forms of memory, may be caused, in part, by altered synaptic plasticity mechanisms in the hippocampus, including long-term potentiation (LTP). To the extent that the mechanisms responsible for LTP can be understood, it may be possible to develop therapeutic approaches to alleviate memory decline in normal ageing.     

Impaired hippocampal long-term potentiation and failure of learning in β1,4-N-acetylgalactosaminyltransferase gene transgenic mice

Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which is considered as a cellular mechanism of learning and memory. In the present study, three types of synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD) and reversal of LTP (depotentiation, DP), in the field excitatory post-synaptic potential in CA1 hippocampal neurons and learning behavior were examined in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice, which showed a marked decrease in b-pathway gangliosides (GQ1b, GT1b and GD1b) in the brain and isolated hippocampus compared with wild-type (WT) mice. The magnitude of the LTP induced by tetanus (100 pulses at 100?Hz) in TG mice was significantly smaller than that in control WT mice, whereas there was no difference in the magnitude of the LTD induced by three short trains of low-frequency stimulation (LFS) (200 pulses at 1?Hz) at 20?min intervals between the two groups of mice. The reduction in the LTP produced by delivering three trains of LFS (200 pulses at 1?Hz, 20?min intervals) was significantly greater in the TG mice than in the WT mice. Learning was impaired in the four-pellet taking test (4PTT) in TG mice, with no significant difference in daily activity or activity during the 4PTT between TG and WT mice. These results suggest that the overexpression of β1,4 GalNAc-T resulted in altered synaptic plasticity of LTP and DP in hippocampal CA1 neurons and learning in the 4PTT, and this is attributable to the shift from b-pathway gangliosides to a-pathway gangliosides.     

Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus

Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.     

Disinhibition Mediates a Form of Hippocampal Long-Term Potentiation in Area CA1

The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.     

A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca²⁺-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca²⁺-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca²⁺-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.     

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.     

Multiple forms of long-term potentiation and multiple regulatory sites of N-methyl-D-aspartate receptors: Role of the redox site

Long-term potentiation (LTP) is a form of synaptic plasticity thought to be involved in learning and memory. Althrough extensively studied, mainly in the CA1 region of the hippocampus, the mechanisms underlying the induction and expression of LTP are poorly elucidated. This is probably due to the fact that LTP is not a unique process and indeed recent studies have shown that several forms of LTP could be generated depending on the experimental conditions. Furthermore, LTP is generally associated with a long-lasting increase of the synaptic efficacy of AMPA receptors but an increasing number of data also suggested that NMDA receptors could be potentiated as well. NMDA receptor responses are modulated by a large number of extracellular and intracellular events, providing additional possibilities for the generation of LTP. The role of these different modulatory sites of the NMDA receptor and their relation with LTP are reviewed with a particular attention to the redox site which seems to be a selective target to distinguish between AMPA and NMDA-LTP. © 1995 John Wiley & Sons, Inc.     

Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory

Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.     

抑郁症模型大鼠学习记忆能力变化研究

为探讨抑郁症发生发展过程中学习记忆能力的变化模式及其可能机制．分别采用21天慢性非预见性刺激法和嗅球切除法建立的抑郁症模型大鼠．运用旷场行为实验（open—field behavior）检测大鼠主动性活动能力,用Morris水迷宫法检测大鼠空间学习记忆能力,HPLC—UV法测定大鼠血清皮质醇含量。电生理法记录海马CA1区LTP与LTD,观察海马神经元的突触可塑性。结果显示：与对照组相比,两种模型的自主活动性、空间探索兴趣和学习能力都明显降低,而记忆的反馈功能没有明显的变化。同时．两种模型大鼠海马神经细胞的突触可塑性显著下降,血清皮质醇的含量则明显上升。提示两种建模方法均导致大鼠产生抑郁症状和学习能力障碍．但对记忆反馈功能无明显影响。     

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.     

β-adrenergic modulation of in vivo long-term potentiation in area CA1 and its role in spatial learning in rats

The hippocampus plays a key role in declarative learning and memory [1]. Hippocampal long-term potentiation (LTP) is a type of synaptic plasticity that has been widely studied as a syn-aptic mechanism underlying learning and memory[27]. It has been reported that in vitro LTP in area CA1 is subjected to b-adrenergic modulation. For example, the theta-pulse stimulation (510 Hz), a neutral frequency not modifying synaptic strength, can elicit a robust LTP in area CA1 in slice when the b-adr…