LTP, post or pre? A look at the evidence for the locus of long-term potentiation.

It seems self-evident that changes in the cellular synaptic function of the brain must underlie the formation and storage of cognitive memories. Because it has been identified as a brain area important in the formation of memory, the hippocampus has been a focus in the study of such synaptic changes. An activity-induced increase in hippocampal synaptic efficacy, known as long-term potentiation (LTP), has been widely studied as a potential substrate for memory. This paper briefly reviews some of the significant progress that has been made in understanding the cellular mechanisms that underlie LTP, including recent experiments dealing with its synaptic locus, or the question of whether the mechanism regulating LTP is pre- or postsynaptic.     

Synaptic mechanisms of associative memory in the amygdala

Do associative learning and synaptic long-term potentiation (LTP) depend on the same cellular mechanisms? Recent work in the amygdala reveals that LTP and Pavlovian fear conditioning induce similar changes in postsynaptic AMPA-type glutamate receptors and that occluding these changes by viral-mediated overexpression of a dominant-negative GluR1 construct attenuates both LTP and fear memory in rats. Novel forms of presynaptic plasticity in the lateral nucleus may also contribute to fear memory formation, bolstering the connection between synaptic plasticity mechanisms and associative learning and memory.     

Use of brain slices to study long-term potentiation and depression as examples of synaptic plasticity.

Brain slices have been responsible for the majority of advances in our understanding of the cellular aspects of altered synaptic strength underlying memory, long-term potentiation (LTP) and long-term depression (LTD), and increases and decreases, respectively, in synaptic strength at glutamatergic synapses. Our current understanding of LTP and LTD has come largely from studies in hippocampal slices. We consider the strengths and limitations of brain slice technology applied to this subject and conclude that they will continue to have an important role in future studies into the cellular machinery underlying changes in synaptic strength.     

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.     

Presynaptic and Postsynaptic Cortical Mechanisms of Chronic Pain

Long-term potentiation (LTP) is a cellular model for learning and memory and believed to be critical for plastic changes in the brain. Depending on the central nervous system region, LTP has been proposed to contribute to many key physiological functions and pathological conditions, such as learning/memory, chronic pain, and drug addiction. While the induction of LTP in general requires activation of postsynaptic glutamate receptors, the expression of LTP can be mediated by postsynaptic mechanisms and/or presynaptic enhancement of glutamate release. In this review, we will evaluate recent progress made in the mechanisms of LTP in the anterior cingulate cortex (ACC) and explore its functional significance in synaptic changes after peripheral injury. Recent findings suggest that while ACC LTP in brain slice preparations is postsynaptically induced and expressed, injury triggered synaptic potentiation in the ACC contains both presynaptic enhancement of glutamate release and postsynaptic potentiation of AMPA receptor-mediated responses. Understanding presynaptic and postsynaptic mechanisms for ACC potentiation may help us to treat chronic pain in near future.     

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.     

Leptin and its role in hippocampal synaptic plasticity

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.     

Functional MRI of long-term potentiation: imaging network plasticity

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.     

The molecular basis of CaMKII function in synaptic and behavioural memory

Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.     

Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.     

Leitmotifs in the biochemistry of LTP induction: amplification, integration and coordination

Hippocampal long-term potentiation (LTP) is a robust and long-lasting form of synaptic plasticity that is the leading candidate for a cellular mechanism contributing to mammalian learning and memory. Investigations over the past decade have revealed that the biochemistry of LTP induction involves mechanisms of great subtlety and complexity. This review highlights themes that have emerged as a result of our increased knowledge of the signal transduction pathways involved in the induction of NMDA receptor-dependent LTP in area CA1 of the hippocampus. Among these themes are signal amplification, signal integration and signal coordination. Here we use these themes as an organizing context for reviewing the profusion of signaling mechanisms involved in the induction of LTP.     

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.     

Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease

Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-D-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91(phox) and p47(phox), both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91(phox) and p47(phox) mutant mice have mild impairments in hippocampus-dependent memory. The gp91(phox) mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47(phox) mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.     

A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells.     

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.     

LTP,memory and structural plasticity

Our current understanding of the mechanisms of information processing and storage in the brain, based on the concept proposed more than fifty years ago by D. Hebb, is that a key role is played by changes in synaptic efficacy induced by coincident pre- and postsynaptic activity. Decades of studies of the properties of long-term potentiation (LTP) have shown that this form of plasticity adequately fulfills these requirements and is likely to contribute to several models of learning and memory. Recent analyses of the molecular events implicated in LTP are consistent with the view that modifications of receptor properties or insertion of new receptors account for the potentiation of synaptic transmission. These experiments, however, have also uncovered an unexpected structural plasticity of synapses. Dendritic spines appear to be dynamic structures that can be formed, modified in their shape or eliminated under the influence of activity. Furthermore, recent studies suggest that LTP, in addition to changes in synaptic function, is also associated with mechanisms of synaptogenesis. We review here the evidence pointing to this activity-dependent remodeling and discuss the possible role of this structural plasticity for synaptic potentiation, learning and memory.     

Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement

Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.     

A fresh look at the role of CaMKII in hippocampal synaptic plasticity and memory

Advances in molecular, genetic, and cell biological techniques have allowed neuroscientists to delve into the cellular machinery of learning and memory. The calcium and calmodulin-dependent kinase type II (CaMKII) is one of the best candidates for being a molecular component of the learning and memory machinery in the mammalian brain. It is present in abundance at synapses and its enzymatic properties and responsiveness to intracellular Ca(2+) fit a model whereby Ca(2+) currents activate the kinase and lead to changes in synaptic efficacy. Indeed, such plastic properties of synapses are thought to be important for memory formation. Genetic analysis of the alpha isoform of CaMKII in mice support the hypothesis that CaMKII signaling is required to initiate the formation of new spatial memories in the hippocampus. CaMKII is also required for the correct induction of long-term potentiation (LTP) in the hippocampus, consistent with the widely held belief that LTP is a mechanism for learning and memory. Recent cell biological, genetic, and physiological analyses suggest that one of the cellular explanations for LTP and CaMKII function might be the trafficking of AMPA-type receptors to synapses in response to neural activity.     

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.     

Extracellular matrix molecules, long-term potentiation, memory consolidation and the brain angiotensin system

Considerable evidence now suggests an interrelationship among long-term potentiation (LTP), extracellular matrix (ECM) reconfiguration, synaptogenesis, and memory consolidation within the mammalian central nervous system. Extracellular matrix molecules provide the scaffolding necessary to permit synaptic remodeling and contribute to the regulation of ionic and nutritional homeostasis of surrounding cells. These molecules also facilitate cellular proliferation, movement, differentiation, and apoptosis. The present review initially focuses on characterizing the ECM and the roles of cell adhesion molecules (CAMs), matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), in the maintenance and degradation of the ECM. The induction and maintenance of LTP is described. Debate continues over whether LTP results in some form of synaptic strengthening and in turn promotes memory consolidation. Next, the contribution of CAMs and TIMPs to the facilitation of LTP and memory consolidation is discussed. Finally, possible roles for angiotensins, MMPs, and tissue plasminogen activators in the facilitation of LTP and memory consolidation are described. These enzymatic pathways appear to be very important to an understanding of dysfunctional memory diseases such as Alzheimer's disease, multiple sclerosis, brain tumors, and infections.