Cellular and molecular mechanisms of memory

There has been nearly a century of interest in the idea that information is encoded in the brain as specific spatio-temporal patterns of activity in distributed networks and stored as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.     

The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity

Synaptic plasticity is a phenomenon contributing to changes in the efficacy of neuronal transmission. These changes are widely believed to be a major cellular basis for learning and memory. Protein phosphorylation is a key biochemical process involved in synaptic plasticity that operates through a tight balance between the action of protein kinases and protein phosphatases (PPs). Although the majority of research in this field has concentrated primarily on protein kinases, the significant role of PPs is becoming increasingly apparent. This review examines one such phosphatase, PP1, and highlights recent advances in the understanding of its intervention in synaptic and structural plasticity and the mechanisms of learning and memory.     

Making memories stick: cell-adhesion molecules in synaptic plasticity

Synapses are adhesive junctions highly specialized for interneuronal signalling in the central nervous system. The strength of the synaptic signal can be modified (synaptic plasticity), a key feature of the cellular changes thought to underlie learning and memory. Cell-adhesion molecules are important constituents of synapses, with well-recognized roles in building and maintaining synaptic structure during brain development. However, growing evidence indicates that cell-adhesion molecules also play important and diverse roles in regulating synaptic plasticity and learning and memory. This review focuses on recent advances in understanding the molecular mechanisms through which adhesion molecules might regulate synaptic plasticity.     

Hebb and homeostasis in neuronal plasticity

The positive-feedback nature of Hebbian plasticity can destabilize the properties of neuronal networks. Recent work has demonstrated that this destabilizing influence is counteracted by a number of homeostatic plasticity mechanisms that stabilize neuronal activity. Such mechanisms include global changes in synaptic strengths, changes in neuronal excitability, and the regulation of synapse number. These recent studies suggest that Hebbian and homeostatic plasticity often target the same molecular substrates, and have opposing effects on synaptic or neuronal properties. These advances significantly broaden our framework for understanding the effects of activity on synaptic function and neuronal excitability.     

The role of synaptic ion channels in synaptic plasticity

The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.     

Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with a multitude of functions. Although Cdk5 is widely expressed, it has been studied most extensively in neurons. Since its initial characterization, the fundamental contribution of Cdk5 to an impressive range of neuronal processes has become clear. These phenomena include neural development, dopaminergic function and neurodegeneration. Data from different fields have recently converged to provide evidence for the participation of Cdk5 in synaptic plasticity, learning and memory. In this review, we consider recent data implicating Cdk5 in molecular and cellular mechanisms underlying synaptic plasticity. We relate these findings to its emerging role in learning and memory. Particular attention is paid to the activation of Cdk5 by p25, which enhances hippocampal synaptic plasticity and memory, and suggests formation of p25 as a physiological process regulating synaptic plasticity and memory.     

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

Synaptic plasticity has a central role in nearly all models of learning and memory. Besides experiments documenting changes in synaptic function during learning, most of the evidence supporting a role for synaptic plasticity in memory comes from manipulations that either enhance or lesion synaptic processes. In the last decade, mouse transgenetics (knock outs and transgenics) have provided compelling evidence that the molecular mechanisms responsible for the induction and stability of synaptic changes have a critical role in the acquisition and storage of information. Here, I will review this literature, with a special focus on studies of hippocampal-dependent learning and memory.     

Glial cells in synaptic plasticity.

Plasticity of synaptic transmission is believed to be the cellular basis for learning and memory, and depends upon different pre- and post-synaptic neuronal mechanisms. Recently, however, an increasing number of studies have implicated a third element in plasticity; the perisynaptic glial cell. Originally glial cells were thought to be important for metabolic maintenance and support of the nervous system. However, work in the past decade has clearly demonstrated active involvement of glia in stability and overall nervous system function as well as synaptic plasticity. Through specific modulation of glial cell function, a wide variety of roles for glia in synaptic plasticity have been uncovered. Furthermore, interesting circumstantial evidence suggests a glial involvement in multiple other types of plasticity. We will discuss recent advances in neuron-glial interactions that take place during synaptic plasticity and explore different plasticity phenomena in which glial cells may be involved.     

d-Serine: A key to synaptic plasticity?

Two discoveries have put d-serine in the spotlight of neuroscience. First, d-serine was detected in brain tissue at high levels. Second, it was found to act on the N-methyl-d-aspartate receptor (NMDAR). This receptor is central to use-dependent synaptic plasticity, the cellular process which is widely believed to underlie learning. The ensuing quest for the mechanisms of d-serine synthesis, release and clearance, as well as for its physiological significance has provided a wealth of experimental evidence implicating d-serine in synaptic plasticity. However some key questions remain unanswered. Which cells release d-serine and upon what stimuli? Is d-serine supply dynamically regulated? What is the fate of released d-serine? Answering these questions appears to be an essential step in our understanding of how NMDARs trigger synaptic plasticity and learning. This review will highlight some recent advances and avenues of enquiry in dynamic d-serine signaling in the mammalian brain with emphasis on neurophysiology.     

Alternative roles for Cdk5 in learning and synaptic plasticity

Protein kinases mediate the intracellular signal transduction pathways controlling synaptic plasticity in the central nervous system. While the majority of protein kinases achieve this function via the phosphorylation of synaptic substrates, some kinases may contribute through alternative mechanisms in addition to enzymatic activity. There is growing evidence that protein kinases may often play structural roles in plasticity as well. Cyclin-dependent kinase 5 (Cdk5) has been implicated in learning and synaptic plasticity. Initial scrutiny focused on its enzymatic activity using pharmacological inhibitors and genetic modifications of Cdk5 cofactors. Quite recently Cdk5 has been shown to govern learning and plasticity via regulation of glutamate receptor degradation, a function that may not dependent on phosphorylation of downstream effectors. From these new studies, two roles emerge for Cdk5 in plasticity: one in which it controls structural plasticity via phosphorylation of synaptic substrates, and a second where it regulates functional plasticity via protein-protein interactions.     

Long-term plasticity at inhibitory synapses

Experience-dependent modifications of neural circuits and function are believed to heavily depend on changes in synaptic efficacy such as LTP/LTD. Hence, much effort has been devoted to elucidating the mechanisms underlying these forms of synaptic plasticity. Although most of this work has focused on excitatory synapses, it is now clear that diverse mechanisms of long-term inhibitory plasticity have evolved to provide additional flexibility to neural circuits. By changing the excitatory/inhibitory balance, GABAergic plasticity can regulate excitability, neural circuit function and ultimately, contribute to learning and memory, and neural circuit refinement. Here we discuss recent advancements in our understanding of the mechanisms and functional relevance of GABAergic inhibitory synaptic plasticity.     

Mapping molecular memory: navigating the cellular pathways of learning

A consolidated map of the signalling pathways that function in the formation of short- and long-term cellular memory could be considered the ultimate means of defining the molecular basis of learning. Research has established that experience-dependent activation of these complex cellular cascades leads to many changes in the composition and functioning of a neuron's proteome, resulting in the modulation of its synaptic strength and structure. However, although generally accepted that synaptic plasticity is the mechanism whereby memories are stored in the brain, there is much controversy over whether the site of this neuronal memory expression is predominantly pre- or postsynaptic. Much of the early research into the neuromolecular mechanisms of memory performed using the model organism, the marine snail Aplysia, has focused on the associated presynaptic events. Recently however, postsynaptic mechanisms have been shown to contribute definitively to long term memory processes, and are in fact critical for persistent learning-induced synaptic changes. In this review, in which we aimed to integrate many of the early and recent advances concerning coordinated neuronal signaling in both the pre- and postsynaptic neurons, we have provided a detailed account of the diverse cellular events that lead to modifications in synaptic strength. Thus, a comprehensive synaptic model is presented that could explain a few of the shortcomings that arise when the presynaptic and postsynaptic changes are considered separately. Although it is clear that there is still much to be learnt and that the exact nature of many of the signalling cascades and their components are yet to be fully understood, this still incomplete but integrated illustrative map of the cellular pathways involved provides an overview which expands understanding of the neuromolecular mechanisms of learning and memory.     

Exploring the Ca2+-dependent synaptic dynamics in vibro-dissociated cells

Dynamic alteration of the synaptic strength is one of the most important processes occurring in the nervous system. Combination of electrophysiology, confocal imaging and molecular biology led to significant advances in this research field. Yet, a progress in this area, in particular in studies of changes in the quantal behavior of central synapses and impact of glial cells on individual synapses, is hampered by technical difficulties of resolving small quantal synaptic currents. In this paper we will show how the technique of non-enzymatic vibro-dissociation, which enables to isolate living neurons avoiding artifacts of cell culture and preserving functional synapse, can be used to obtain a valuable information on fine details and mechanisms of synaptic plasticity. In particular, we will describe our recent results on Ca²⁺-dependent modulation of the postsynaptic AMPA and NMDA receptors in the individual synaptic boutons.     

Pain Facilitation and Activity-Dependent Plasticity in Pain Modulatory Circuitry: Role of BDNF-TrkB Signaling and NMDA Receptors

Pain modulatory circuitry in the brainstem exhibits considerable synaptic plasticity. The increased peripheral neuronal barrage after injury activates spinal projection neurons that then activate multiple chemical mediators including glutamatergic neurons at the brainstem level, leading to an increased synaptic strength and facilitatory output. It is not surprising that a well-established regulator of synaptic plasticity, brain-derived neurotrophic factor (BDNF), contributes to the mechanisms of descending pain facilitation. After tissue injury, BDNF and TrkB signaling in the brainstem circuitry is rapidly activated. Through the intracellular signaling cascade that involves phospholipase C, inositol trisphosphate, protein kinase C, and nonreceptor protein tyrosine kinases; N-methyl-D-aspartate (NMDA) receptors are phosphorylated, descending facilitatory drive is initiated, and behavioral hyperalgesia follows. The synaptic plasticity observed in the pain pathways shares much similarity with more extensively studied forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), which typically express NMDA receptor dependency and regulation by trophic factors. However, LTP and LTD are experimental phenomena whose relationship to functional states of learning and memory has been difficult to prove. Although mechanisms of synaptic plasticity in pain pathways have typically not been related to LTP and LTD, pain pathways have an advantage as a model system for synaptic modifications as there are many well-established models of persistent pain with clear measures of the behavioral phenotype. Further studies will elucidate cellular and molecular mechanisms of pain sensitization and further our understanding of principles of central nervous system plasticity and responsiveness to environmental challenge.     

Gene control of synaptic plasticity and memory formation: implications for diseases and therapeutic strategies

There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.     

长时程抑制在学习记忆中的作用及其分子机制的研究进展

长时程抑制(long term depression,LTD)是突触可塑性的重要形式之一,并且与学习记忆存在着密切的关系。近10年有关LTD的研究表明：LTD诱导和维持过程所必需的许多分子在进化上具有高度的保守性,多种细胞膜受体、细胞信号转导通路级联成分、基因表达的转录调节因子与学习记忆的调控有关,这些研究结果为我们阐明脑的正常功能,治疗中枢系统神经疾病,提供了新的线索。     

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.     

Time and tide in cerebellar memory formation

The notion that the olivocerebellar system is crucial for motor learning is well established. In recent years, it has become evident that there can be many forms of both synaptic and non-synaptic plasticity within this system and that each might have a different role in developing and maintaining motor learning across a wide range of tasks. There are several possible molecular and cellular mechanisms that could underlie adaptation of the vestibulo-ocular reflex and eyeblink conditioning. Although causal relationships between particular cellular processes and individual components of a learned behaviour have not been demonstrated unequivocally, an overall picture is emerging that the different types and sites of cellular plasticity relate importantly to the stage of learning and/or its temporal specifics.     

Modulation of Synaptic Plasticity by Exercise Training as a Basis for Ischemic Stroke Rehabilitation

In recent years, rehabilitation of ischemic stroke draws more and more attention in the world, and has been linked to changes of synaptic plasticity. Exercise training improves motor function of ischemia as well as cognition which is associated with formation of learning and memory. The molecular basis of learning and memory might be synaptic plasticity. Research has therefore been conducted in an attempt to relate effects of exercise training to neuroprotection and neurogenesis adjacent to the ischemic injury brain. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved in modulation of synaptic plasticity by exercise training. This review shows the pathological process of synaptic dysfunction in ischemic roughly and then discusses the effects of exercise training on scaffold proteins and regulatory protein expression. The expression of scaffold proteins generally increased after training, but the effects on regulatory proteins were mixed. Moreover, the compositions of postsynaptic receptors were changed and the strength of synaptic transmission was enhanced after training. Finally, the recovery of cognition is critically associated with synaptic remodeling in an injured brain, and the remodeling occurs through a number of local regulations including mRNA translation, remodeling of cytoskeleton, and receptor trafficking into and out of the synapse. We do provide a comprehensive knowledge of synaptic plasticity enhancement obtained by exercise training in this review.     

In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus

Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snail Aplysia and in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation in Aplysia and suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.