短时程突触可塑性的功能意义

短时程的突触可塑性是突触可塑性的一种重要表现形式,对实现神经系统的正常功能起着重要作用.突触的短时程可塑性能够加强突触传递的确定性,调节大脑皮层兴奋和抑制之间的平衡,形成神经活动的时间、空间特性,形成并调节皮层丘脑网络的同步振荡.突触的短时程可塑性可能也参与了注意、启动效应、睡眠节律和学习记忆等神经系统高级功能的实现.     

Structural Components of Synaptic Plasticity and Memory Consolidation

Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain.Santiago Ramón y Cajal (1894) used the insights provided by his remarkable light microscopic observations of neurons selectively stained with the Golgi method to propose the first cellular theory of memory storage as an anatomical change in the functional connections between nerve cells, later called synapses (Sherrington 1897). For most of the last century, chemical synapses were thought to convey information in only one direction—from the presynaptic to the postsynaptic neuron. It now is clear that synaptic transmission is a bidirectional and self-modifiable form of cell–cell communication (Peters et al. 1976; Jessell and Kandel 1993). This appreciation of reciprocal signaling between pre- and postsynaptic elements is consistent with other forms of intercellular communication and provides a conceptual framework for understanding memory-induced changes in the structure of the synapse. Indeed, an increasing body of evidence suggests that trans-synaptic signaling and coordinated recruitment of pre- and postsynaptic mechanisms underlie consolidation of both implicit and explicit forms of memory storage (Marrone 2005; Hawkins et al. 2006; Bailey et al. 2008).Studies in a variety of systems have found that molecular mechanisms of consolidation and long-term storage of memory begin at the level of the synapse. Existing proteins are modified, signals are sent back to the nucleus so that specific genes are expressed, and gene products are transported back to the synapse where the local synthesis of new protein is triggered to allow for the remodeling, addition, and elimination of synapses (Bailey and Kandel 1985; Bailey et al. 1996; Kandel 2001; Bourne and Harris 2008, 2012). These structural components of synaptic plasticity are thought to represent a cellular change that contributes to both implicit and explicit memory consolidation (Greenough and Bailey 1988; Bailey and Kandel 1993; Bailey et al. 2005; Bourne and Harris 2008, 2012). The association between alterations in the structure and/or number of synapses and memory storage has led to numerous studies regarding the signaling pathways that might couple molecular changes to structural changes. In addition, parallel homeostatic mechanisms have been identified that can trigger synaptic scaling, which serves to stabilize the strengthened synapses while weakening or eliminating other synapses, thus providing specificity during memory consolidation (Bourne and Harris 2011; Schacher and Hu 2014).In this review, we compare and contrast structural changes at the synapse during both implicit and explicit memory consolidation, as well as the molecular signaling pathways that initiate the learning-induced structural changes versus those that serve to maintain these changes over time. Toward that end, we will focus on two experimental model systems and several prototypic forms of synaptic plasticity that we have worked on and that have been extensively studied as representative examples of memory storage: long-term habituation and sensitization of the gill-withdrawal reflex in Aplysia. These are examples of implicit memory consolidation and hippocampal-based long-term potentiation (LTP) and long-term depression (LTD), as candidate mechanisms for the synaptic plasticity underlying explicit memory storage in mammals. These will serve as useful points of comparison to consider similarities, differences, and still-existing limitations in our understanding of the functional significance of the structural synaptic plasticity recruited during the consolidation of both implicit and explicit forms of memory.     

Pentylenetetrazol-Induced Epileptiform Activity Affects Basal Synaptic Transmission and Short-Term Plasticity in Monosynaptic Connections

Epileptic activity is generally induced in experimental models by local application of epileptogenic drugs, including pentylenetetrazol (PTZ), widely used on both vertebrate and invertebrate neurons. Despite the high prevalence of this neurological disorder and the extensive research on it, the cellular and molecular mechanisms underlying epileptogenesis still remain unclear. In this work, we examined PTZ-induced neuronal changes in Helix monosynaptic circuits formed in vitro, as a simpler experimental model to investigate the effects of epileptiform activity on both basal release and post-tetanic potentiation (PTP), a form of short-term plasticity. We observed a significant enhancement of basal synaptic strength, with kinetics resembling those of previously described use-dependent forms of plasticity, determined by changes in estimated quantal parameters, such as the readily releasable pool and the release probability. Moreover, these neurons exhibited a strong reduction in PTP expression and in its decay time constant, suggesting an impairment in the dynamic reorganization of synaptic vesicle pools following prolonged stimulation of synaptic transmission. In order to explain this imbalance, we determined whether epileptic activity is related to the phosphorylation level of synapsin, which is known to modulate synaptic plasticity. Using western blot and immunocytochemical staining we found a PTZ-dependent increase in synapsin phosphorylation at both PKA/CaMKI/IV and MAPK/Erk sites, both of which are important for modulating synaptic plasticity. Taken together, our findings suggest that prolonged epileptiform activity leads to an increase in the synapsin phosphorylation status, thereby contributing to an alteration of synaptic strength in both basal condition and tetanus-induced potentiation.     

Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity

In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational studies of sensory processing in neocortical network models equipped with synaptic plasticity.     

Nanoscale Remodeling of Functional Synaptic Vesicle Pools in Hebbian Plasticity

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一次性电击引起大鼠脑内突触结构可塑性变化的定量观察

运用电镜,对一次性电击引起大鼠脑内Ｇｒａｙ Ⅰ型突触界面某些结构的变化进行了定量观察。在海马ＣＡ３区,突触后膜致密物质显著增厚（Ｐ〈０．０５）,突触间隙宽度极显著增宽（Ｐ〈０．０１）;在大脑皮层感觉运动区,突触界面曲率显著变大（Ｐ〈０．０５）。突触界面弯曲类型无显著性差异。结果提示：一次性电击可以引起大鼠脑内突触界面结构发生可塑性变化。     

Repair and Regeneration of Functional Synaptic Connections: Cellular and Molecular Interactions in the Leech

A major problem for neuroscience has been to find a means to achieve reliable regeneration of synaptic connections following injury to the adult CNS. This problem has been solved by the leech, where identified neurons reconnect precisely with their usual targets following axotomy, re-establishing in the adult the connections formed during embryonic development.It cannot be assumed that once axons regenerate specific synapses, function will be restored. Recent work on the leech has shown following regeneration of the synapse between S-interneurons, which are required for sensitization of reflexive shortening, a form of non-associative learning, the capacity for sensitization is delayed.The steps in repair of synaptic connections in the leech are reviewed, with the aim of understanding general mechanisms that promote successful repair. New results are presented regarding the signals that regulate microglial migration to lesions, a first step in the repair process. In particular, microglia up to 900 m from the lesion respond within minutes by moving rapidly toward the injury, controlled in part by nitric oxide (NO), which is generated immediately at the lesion and acts via a soluble guanylate cyclase (sGC). The cGMP produced remains elevated for hours after injury. The relationship of microglial migration to axon outgrowth is discussed.     

Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer's disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.     

Regeneration of Identified Neurons and Their Synaptic Connections in the Central Nervous System of Aplysia

SYNOPSIS. In the CNS of Aplysia the number and sequence of lesionsinfluence the regeneration of identified neurons and their synapticconnections The left pleural ganglion giant neuron (LGC) failsto regenerate its severed axon following crushes of the cerebropleural (C-PL) connectses A conditioning lesion paradigm inwhich first a foot nerve and then 10 days later, the left C-PLconnective is crushed, results in the LGC regenerating its axonSynaptic inputs from identified neurons in the cerebral ganglionrarely regenerate when only the C-PL connectives are crushedConditioning lesions also result in the regeneration of synapticconnections from the cerebral A neurons Multiple and sequentiallesions appear to be more effective than single lesions in promotingboth axonal regeneration and synapse formation The possiblemechanisms by which axonal regeneration and synaptogenesis arecontrolled are discussed.     

AMPA受体的磷酸化与突触可塑性

突触可塑性在学习记忆中发挥了重要作用,AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid,AMPA)受体功能和运输的调节是突触可塑性机制研究的重要环节。在突触可塑性发生过程中,激酶和磷酸酶能够调节AMPA受体C末端的磷酸化水平,进而影响AMPA受体运输。对于AMPA受体磷酸化的研究能够加深我们对突触可塑性机制的理解。     

Proteolytic Remodeling of the Synaptic Cell Adhesion Molecules (CAMs) by Metzincins in Synaptic Plasticity

Cell adhesion molecules participate in the formation, maturation, function and plasticity of synaptic connections. The growing body of evidence indicates that in the regulation of the synaptic plasticity, in which these molecules play pivotal role, also the proteolytic processes are involved. This review focuses on extracellular proteolysis of the cell adhesion molecules by specific subgroup of the matrix metalloproteinases, a disintegrin and metalloproteases and a disintegrin and metalloproteinase with thrombospondin motifs, jointly referred to as metzincins, in driving coordinated synaptic structural and functional modifications underlying synaptic plasticity in the adult brain.     

Structural and Functional Studies of the Phage Sf6 Terminase Small Subunit Reveal a DNA-Spooling Device Facilitated by Structural Plasticity

In many DNA viruses, genome packaging is initiated by the small subunit of the packaging terminase, which specifically binds to the packaging signal on viral DNA and directs assembly of the terminase holoenzyme. We have experimentally mapped the DNA-interacting region on Shigella virus Sf6 terminase small subunit gp1, which occupies extended surface areas encircling the gp1 octamer, indicating that DNA wraps around gp1 through extensive contacts. High‐resolution structures reveal large-scale motions of the gp1 DNA-binding domain mediated by the curved helix formed by residues 54–81 and an intermolecular salt bridge formed by residues Arg67 and Glu73, indicating remarkable structural plasticity underlying multivalent, pleomorphic gp1:DNA interactions. These results provide spatial restraints for protein:DNA interactions, which enable construction of a three-dimensional pseudo-atomic model for a DNA-packaging initiation complex assembled from the terminase small subunit and the packaging region on viral DNA. Our results suggest that gp1 functions as a DNA-spooling device, which may transform DNA into a specific architecture appropriate for interaction with and cleavage by the terminase large subunit prior to DNA translocation into viral procapsid. This may represent a common mechanism for the initiation step of DNA packaging in tailed double‐stranded DNA bacterial viruses.     

Refinement and Pattern Formation in Neural Circuits by the Interaction of Traveling Waves with Spike-Timing Dependent Plasticity

Traveling waves in the developing brain are a prominent source of highly correlated spiking activity that may instruct the refinement of neural circuits. A candidate mechanism for mediating such refinement is spike-timing dependent plasticity (STDP), which translates correlated activity patterns into changes in synaptic strength. To assess the potential of these phenomena to build useful structure in developing neural circuits, we examined the interaction of wave activity with STDP rules in simple, biologically plausible models of spiking neurons. We derive an expression for the synaptic strength dynamics showing that, by mapping the time dependence of STDP into spatial interactions, traveling waves can build periodic synaptic connectivity patterns into feedforward circuits with a broad class of experimentally observed STDP rules. The spatial scale of the connectivity patterns increases with wave speed and STDP time constants. We verify these results with simulations and demonstrate their robustness to likely sources of noise. We show how this pattern formation ability, which is analogous to solutions of reaction-diffusion systems that have been widely applied to biological pattern formation, can be harnessed to instruct the refinement of postsynaptic receptive fields. Our results hold for rich, complex wave patterns in two dimensions and over several orders of magnitude in wave speeds and STDP time constants, and they provide predictions that can be tested under existing experimental paradigms. Our model generalizes across brain areas and STDP rules, allowing broad application to the ubiquitous occurrence of traveling waves and to wave-like activity patterns induced by moving stimuli.     

Structural Damage Induced by Peroxidation May Account for Functional Impairment of Heavy Synaptic Mitochondria

Coenzyme Q distribution, as well as respiratory chain features, in rat brain mitochondria depend on mitochondrial subpopulation, brain region and age. Heavy mitochondria (HM) usually display the lowest content of respiratory components and the lowest enzymatic activities and it has been suggested that they represent the oldest mitochondrial population. In this study, we confirmed that HM are considerably compromised in their structure. In fact, HM showed to have the highest hydroperoxide content and the most consistent modifications in their fatty acid pattern with wide loss of fatty acids (or part of them) in the phospholipid moiety. Such situation could explain the typical impairment of HM and could support the hypothesis that they represent an old mitochondrial population.     

DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain

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Highlights? DCC and netrin-1 are enriched at synapses in the adult mouse forebrain ? DCC is enriched in the PSD and regulates dendritic spine morphology ? LTP induction and memory formation require DCC expression by neurons ? DCC activation of Src is required for NMDAR-dependent LTP in adult CNS     

Spike-Timing Dependence of Structural Plasticity Explains Cooperative Synapse Formation in the Neocortex

Structural plasticity governs the long-term development of synaptic connections in the neocortex. While the underlying processes at the synapses are not fully understood, there is strong evidence that a process of random, independent formation and pruning of excitatory synapses can be ruled out. Instead, there must be some cooperation between the synaptic contacts connecting a single pre- and postsynaptic neuron pair. So far, the mechanism of cooperation is not known. Here we demonstrate that local correlation detection at the postsynaptic dendritic spine suffices to explain the synaptic cooperation effect, without assuming any hypothetical direct interaction pathway between the synaptic contacts. Candidate biomolecular mechanisms for dendritic correlation detection have been identified previously, as well as for structural plasticity based thereon. By analyzing and fitting of a simple model, we show that spike-timing correlation dependent structural plasticity, without additional mechanisms of cross-synapse interaction, can reproduce the experimentally observed distributions of numbers of synaptic contacts between pairs of neurons in the neocortex. Furthermore, the model yields a first explanation for the existence of both transient and persistent dendritic spines and allows to make predictions for future experiments.     

FHL2通过相互作用抑制Id2的功能活性

分化抑制蛋白2（Id2）通过抑制碱性螺旋-环-螺旋（bHLH）类转录因子的功能活性调控多种组织细胞的分化发育,并参与人类多种肿瘤的发生与进展.Id2相互作用蛋白可能调控其翻译后的功能活性．本研究以HLH结构域缺失的Id2作为诱饵蛋白,采用酵母双杂交方法对MCF-7 cDNA文库进行筛选,识别了1个新的Id2相互作用蛋白FHL2 (属于LIM蛋白家族的一员),哺乳动物双杂交实验系统验证了Id2与FHL2之间的相互作用,同时证实,该作用不依赖于Id2中的HLH结构域;GST-pulldown、免疫共沉淀方法,进一步证实FHL2/Id2之间的相互作用;免疫荧光共定位实验结果证实,FHL2/Id2相互作用主要发生在细胞核内;共转染实验结果发现,FHL2通过相互作用阻抑了Id2对bHLH类转录因子E47的功能抑制活性．总之,本研究识别了1个新的Id2相互作用蛋白FHL2,通过直接的相互作用,FHL2抑制了Id2的功能活性,FHL2可能参与调控Id2介导的细胞分化与发育过程,并可能参与肿瘤的发生与进展．