Synaptic cell adhesion

Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that include neurexins and neuroligins, Ig-domain proteins such as SynCAMs, receptor phosphotyrosine kinases and phosphatases, and several leucine-rich repeat proteins have been identified. These synaptic cell adhesion molecules use characteristic extracellular domains to perform complementary roles in organizing synaptic junctions that are only now being revealed. The importance of synaptic cell adhesion molecules for brain function is highlighted by recent findings implicating several such molecules, notably neurexins and neuroligins, in schizophrenia and autism.     

Synaptic adhesion molecules

Formation, differentiation and plasticity of synapses, the specialized cell-cell contacts through which neurons communicate, all require interactions between pre- and post-synaptic partners. Several synaptically localized adhesion molecules potentially capable of mediating these interactions have been identified recently. Functional studies suggest roles for some of them in target recognition (e.g. SYG-1 and sidekicks), formation and alignment of synaptic specializations (e.g. SynCAM, neuroligin and neurexin), and regulation of synaptic structure and function (e.g. cadherins and syndecan).     

神经细胞粘附分子与记忆

记忆的形成阶段包含着神经元突触的可塑性变化过程.近年来的研究表明,神经细胞粘附分子可同时增进突触的可塑性和维持突触结构的稳定性.许多研究证实神经细胞粘附分子对与学习和记忆相关的过程起着一定的调节作用.     

短时程突触可塑性研究概况

突触可塑性是神经系统所具有的重要特征,也是神经系统实现其功能的重要保障。按照持续的时间划分,突触可塑性可分为短时程突触可塑性和长时程突触可塑性。短时程突触可塑性包括短时程增强和短时程压抑两种类型。与长时程突触可塑性不同,短时程突触可塑性的产生主要依赖于神经递质释放概率的变化,其往往决定神经回路的信息处理和反应模式,不仅直接参与了对输入信号的识别和处理,而且还可对长时程突触可塑性的表达产生重要影响。     

Synaptic signalling in cerebellar plasticity

A major goal of learning and memory research is to correlate the function of molecules with the behaviour of organisms. The beautiful laminar structure of the cerebellar cortex lends itself to the study of synaptic plasticity, because its clearly defined patterns of neurons and their synapses form circuits that have been implicated in simple motor behaviour paradigms. The best understood in terms of molecular mechanism is the parallel fibre-Purkinje cell synapse, where presynaptic long-term potentiation and postsynaptic long-term depression and potentiation finely tune cerebellar output. Our understanding of these forms of plasticity has mostly come from the electrophysiological and behavioural analysis of knockout mutant mice, but more recently the knock-in of synaptic molecules with mutated phosphorylation sites and binding domains has provided more detailed insights into the signalling events. The present review details the major forms of plasticity in the cerebellar cortex, with particular attention to the membrane trafficking and intracellular signalling responsible. This overview of the current literature suggests it will not be long before the involvement of the cerebellum in certain motor behaviours is fully explained in molecular terms.     

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.     

Activity-regulated N-cadherin endocytosis

Enduring forms of synaptic plasticity are thought to require ongoing regulation of adhesion molecules, such as N-cadherin, at synaptic junctions. Little is known about the activity-regulated trafficking of adhesion molecules. Here we demonstrate that surface N-cadherin undergoes a surprisingly high basal rate of internalization. Upon activation of NMDA receptors (NMDAR), the rate of N-cadherin endocytosis is significantly reduced, resulting in an accumulation of N-cadherin in the plasma membrane. Beta-catenin, an N-cadherin binding partner, is a primary regulator of N-cadherin endocytosis. Following NMDAR stimulation, beta-catenin accumulates in spines and exhibits increased binding to N-cadherin. Overexpression of a mutant form of beta-catenin, Y654F, prevents the NMDAR-dependent regulation of N-cadherin internalization, resulting in stabilization of surface N-cadherin molecules. Furthermore, the stabilization of surface N-cadherin blocks NMDAR-dependent synaptic plasticity. These results indicate that NMDAR activity regulates N-cadherin endocytosis, providing a mechanistic link between structural plasticity and persistent changes in synaptic efficacy.     

Myosin IIb-dependent Regulation of Actin Dynamics Is Required for N-Methyl-d-aspartate Receptor Trafficking during Synaptic Plasticity

N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.     

Cell adhesion molecules: signalling functions at the synapse

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.     

Synaptic plasticity in drug reward circuitry

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.     

Selective Decline of Synaptic Protein Levels in the Frontal Cortex of Female Mice Deficient in the Extracellular Metalloproteinase ADAMTS1

The chondroitin sulfate-bearing proteoglycans, also known as lecticans, are a major component of the extracellular matrix (ECM) in the central nervous system and regulate neural plasticity. Growing evidence indicates that endogenous, extracellular metalloproteinases that cleave lecticans mediate neural plasticity by altering the structure of ECM aggregates. The bulk of this in vivo data examined the matrix metalloproteinases, but another metalloproteinase family that cleaves lecticans, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), modulates structural plasticity in vitro, although few in vivo studies have tested this concept. Thus, the purpose of this study was to examine the neurological phenotype of a mouse deficient in ADAMTS1. Adamts1 mRNA was absent in the ADAMTS1 null mouse frontal cortex, but there was no change in the abundance or proteolytic processing of the prominent lecticans brevican and versican V2. However, there was a marked increase in the perinatal lectican neurocan in juvenile ADAMTS1 null female frontal cortex. More prominently, there were declines in synaptic protein levels in the ADAMTS1 null female, but not male, frontal cortex beginning at postnatal day 28. These synaptic marker declines did not affect learning or memory in the adult female ADAMTS1 null mice when tested with the radial-arm water maze. These results indicate that in vivo Adamts1 knockout leads to sexual dimorphism in frontal cortex synaptic protein levels. Since changes in lectican abundance and proteolytic processing did not accompany the synaptic protein declines, ADAMTS1 may play a nonproteolytic role in regulating neural plasticity.     

The Relationship Between Adhesion Molecules and Neuronal Plasticity

1. It is presently widely assumed that structural reorganization of synaptic architectures subserves the functional gains that define certain neuronal plasticities.2. While target molecules thought to participate in such morphological dynamics are not well defined, growing evidence suggests a pivotal role for cell adhesion molecules.3. Herein, brief discussions are presented on (i) the history of how adhesion molecules became implicated in plasticity and memory processes, (ii) the general biology of some of the major classes of such molecules, and (iii) the future of the adhesion molecule/plasticity relationship.     

Synaptic growth: dancing with adducin

Manipulations of the actin-capping protein adducin in Drosophila and mammalian neurons provide new insights into the mechanisms linking structural changes to synaptic plasticity and learning. Adducin regulates synaptic remodeling, providing a molecular switch that controls synaptic growth versus disassembly during plasticity.     

神经粘附分子CHL1在神经系统中的研究进展

粘附分子通过介导细胞间相互作用发挥其在发育、再生和突触修饰等方面的重要作用.神经细胞粘附分子CHL1(close homologue of L1)是近年发现的粘附分子,属于粘附分子免疫球蛋白超家族,集中表达于神经系统,通过亲异性作用(heterophilic interaction)介导细胞与细胞、细胞与胞外基质的相互作用,进而参与神经系统的发育、轴突的生长、迁移及导向等过程.     

Soft-bound Synaptic Plasticity Increases Storage Capacity

Accurate models of synaptic plasticity are essential to understand the adaptive properties of the nervous system and for realistic models of learning and memory. Experiments have shown that synaptic plasticity depends not only on pre- and post-synaptic activity patterns, but also on the strength of the connection itself. Namely, weaker synapses are more easily strengthened than already strong ones. This so called soft-bound plasticity automatically constrains the synaptic strengths. It is known that this has important consequences for the dynamics of plasticity and the synaptic weight distribution, but its impact on information storage is unknown. In this modeling study we introduce an information theoretic framework to analyse memory storage in an online learning setting. We show that soft-bound plasticity increases a variety of performance criteria by about 18% over hard-bound plasticity, and likely maximizes the storage capacity of synapses.     

PSA-NCAM: Synaptic functions mediated by its interactions with proteoglycans and glutamate receptors

Dynamic regulation of glycosylation of the neural cell adhesion molecule (NCAM) by an unusual large negatively charged polysialic acid (PSA) is the major prerequisite for correct formation of brain circuitries during development and for normal synaptic plasticity, learning and memory in the adult. Traditionally, PSA is viewed as a de-adhesive highly hydrated molecule, which interferes with cell adhesion and promotes cellular/synaptic dynamics by steric hindrance. Analysis of synaptic functions of PSA-NCAM highlighted additional features of this molecule. First, PSA promotes interaction of NCAM with heparan sulfate proteoglycans and thus stimulates synaptogenesis. Second, PSA-NCAM modulates glutamate receptors: it restrains activity of extrasynaptic GluN2B-containing NMDA receptors and facilitates activity of a subset of AMPA receptors. Perturbation in polysialylation and/or NCAM expression in mouse models recapitulates many symptoms of human brain disorders such as schizophrenia, depression, anxiety and Alzheimer's disease.     

LAR-RPTPs: synaptic adhesion molecules that shape synapse development

The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated that LAR-RPTP family members are also involved in diverse synaptic functions, playing a role in synaptic adhesion pathways together with a host of distinct transmembrane proteins and serving as major synaptic adhesion molecules in governing pre- and postsynaptic development, dysfunctions of which may underlie various disorders. This review highlights the emerging role of LAR-RPTPs as synapse organizers in orchestrating synapse development.     

长时程突触可塑性中的突触标识

神经元长时程突触可塑性是学习和记忆的基础,神经元长时程突触可塑性的维持依赖于基因的转录和蛋白质合成.然而,这些转录产物和新合成的蛋白质是如何从胞体运输到突触点,还不甚清楚.近年来的研究显示,当长时程突触可塑性发生时,被激活的突触能通过建立突触标记(synaptic tag)来识别、捕捉和利用其所需要的基因产物,以维持突触可塑性的长时程变化.这一过程或现象被称为突触标识(synaptic tagging).本文就近年来突触标识的研究进展作一概述.     

Synaptic destabilization by neuronal Nogo-A

Formation and maintenance of a neuronal network is based on a balance between plasticity and stability of synaptic connections. Several molecules have been found to regulate the maintenance of excitatory synapses but nothing is known about the molecular mechanisms involved in synaptic stabilization versus disassembly at inhibitory synapses. Here, we demonstrate that Nogo-A, which is well known to be present in myelin and inhibit growth in the adult CNS, is present in inhibitory presynaptic terminals in cerebellar Purkinje cells at the time of Purkinje cell-Deep Cerebellar Nuclei (DCN) inhibitory synapse formation and is then downregulated during synapse maturation. We addressed the role of neuronal Nogo-A in synapse maturation by generating several mouse lines overexpressing Nogo-A, starting at postnatal ages and throughout adult life, specifically in cerebellar Purkinje cells and their terminals. The overexpression of Nogo-A induced a progressive disassembly, retraction and loss of the inhibitory Purkinje cell terminals. This led to deficits in motor learning and coordination in the transgenic mice. Prior to synapse disassembly, the overexpression of neuronal Nogo-A led to the downregulation of the synaptic scaffold proteins spectrin, spectrin-E and β-catenin in the postsynaptic neurons. Our data suggest that neuronal Nogo-A might play a role in the maintenance of inhibitory synapses by modulating the expression of synaptic anchoring molecules. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Dynamic aspects of cadherin-mediated adhesion in synapse development and plasticity

Cadherins are calcium-dependent cell adhesion molecules that are enriched at synapses. Recent studies indicate important functional roles in synaptic targeting during brain development, and in regulating functional and structural aspects of synaptic plasticity and neural repair throughout life.