Polysialic acid and activity-dependent synapse remodeling

Polysialic acid (PSA) is a large carbohydrate added post-translationally to the extracellular domain of the Neural Cell Adhesion Molecule (NCAM) that influences its adhesive and other functional properties. PSA-NCAM is widely distributed in the developing nervous system where it promotes dynamic cell interactions, like those responsible for axonal growth, terminal sprouting and target innervation. Its expression becomes restricted in the adult nervous system where it is thought to contribute to various forms of neuronal and glial plasticity. We here review evidence, obtained mainly from hypothalamic neuroendocrine centers and the olfactory system, that it intervenes in structural synaptic plasticity and accompanying neuronal-glial transformations, making possible the formation and elimination of synapses that occur under particular physiological conditions.     

MicroRNA与神经系统重大疾病

目前有研究证实microRNA参与了神经系统生长发育和生理功能的调控,它也与可塑性障碍性疾病、神经系统退行性疾病、神经系统肿瘤、脑血管疾病等重大疾病的发生发展相关．随着microRNA研究领域的发展,一些重大神经系统疾病的相关发病机制将有可能被阐释．     

Nitric oxide: an unconventional messenger in the nervous system of an orthopteroid insect

Nitric oxide (NO) is a membrane-permeant messenger molecule generated from the amino acid L-arginine. NO can activate soluble guanylyl cyclase leading to the formation of cyclic GMP (cGMP) in target cells. In the nervous system, NO/cGMP signalling is thought to play essential roles in synaptic plasticity during development and also in the mature animal. This paper examines biochemical, cell biological, and physiological investigations of NO/cGMP signalling in the nervous system of the locust, a commonly used neurobiological preparation. Biochemical investigations suggest that an identical enzyme is responsible for both NO synthase (NOS) and NADPH-diaphorase activity after tissue fixation. Immunocytochemical staining of an olfactory center in the locust brain shows that NOS-immunoreactivity colocalizes with NADPH-diaphorase at the cellular level. The cytochemical staining of NO donor and target cells in adult animals suggests functions in olfaction, vision, and sensorimotor integration. During development, NO is implicated in axonal outgrowth and synaptogenesis. The cellular distribution of NO-responsive cells in neural circuits reflects potential functions of NO as a retrograde synaptic messenger, as an intracellular messenger, and as a lateral diffusible messenger independent of conventional synaptic connectivity.     

An in vitro study of long-term potentiation in the carp (Cyprinus carpio L.) olfactory bulb

Long-term potentiation (LTP) of synaptic transmission is considered a cellular mechanism for neural plasticity and memory formation. Previously, we showed that in the carp olfactory bulb, LTP occurs at the dendrodendritic mitral-to-granule cell synapse following tetanic electrical stimulation applied to the olfactory tract, and suggested that it is involved in the process of olfactory memory formation. As a first step towards understanding mechanisms underlying plasticity at this synapse, we examined the effects of various drugs (glutamate and GABA receptor agonists and antagonists, noradrenaline, and drugs affecting cAMP signaling) on dendrodendritic mitral-to-granule cell synaptic transmission in an in vitro preparation. Two forms of LTP are involved: a postsynaptic form (tetanus-evoked LTP) and a presynaptic form. The postsynaptic form is evoked at the granule cell dendrite following tetanic olfactory tract stimulation and is suppressed by the NMDA receptor antagonist, D-AP5, enhanced by noradrenaline, and occluded by the metabotropic glutamate receptor agonist, trans-ACPD. The presynaptic form occurs at the mitral cell dendrite following blockade of the GABA_A receptor by picrotoxin and bicuculline, or via activation of cAMP signaling by forskolin and 8-Br-cAMP.     

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.     

The perineuronal net component of the extracellular matrix in plasticity and epilepsy

During development the extracellular matrix (ECM) of the central nervous system (CNS) facilitates proliferation, migration, and synaptogenesis. In the mature nervous system due to changes in the ECM it provides structural stability and impedes proliferation, migration, and synaptogensis. The perineuronal net (PN) is a specialized ECM structure found primarily surrounding inhibitory interneurons where it forms a mesh-like structure around points of synaptic contact. The PN organizes the extracellular space by binding multiple components of the ECM and bringing them into close proximity to the cell membrane, forming dense aggregates surrounding synapses. The PN is expressed late in postnatal development when the nervous system is in the final stages of maturation and the critical periods are closing. Once fully expressed the PN envelopes synapses and leads to decreased plasticity and increases synaptic stability in the CNS. Disruptions in the PN have been studied in a number of disease states including epilepsy. Epilepsy is one of the most common neurologic disorders characterized by excessive neuronal activity which results in recurrent spontaneous seizures. A shift in the delicate balance between excitation and inhibition is believed to be one of the underlying mechanisms in the development of epilepsy. During epileptogenesis, the brain undergoes numerous changes including synaptic rearrangement and axonal sprouting, which require structural plasticity. Because of the PNs location around inhibitory cells and its role in limiting plasticity, the PN is an important candidate for altering the progression of epilepsy. In this review, an overview of the ECM and PN in the CNS will be presented with special emphasis on potential roles in epileptogenesis.     

中枢神经系统中的胃泌素释放肽：在厌恶性情绪记忆中的作用及机制研究

胃泌素释放肽(gastrin-releasing peptide,GRP)是蛙皮素(bombesin,BB/BN)在哺乳动物中的同系物,在中枢神经系统中广泛分布,是一种重要的脑内神经调质,参与动物的多种生理功能和本能行为,在大脑的高级功能方面也发挥一定的作用.在神经系统中,随着GRP水平的改变,动物的记忆特别是与恐惧、焦虑相关记忆的形成、巩固和消退以及突触可塑性均发生不同程度的变化.GRP及其受体还被认为与神经系统性疾病有关,是潜在的神经系统性疾病的治疗靶点,但其相关的机制尚未明确.很多研究者基于不同实验方法提出了相关假设.本文从传统药理学、遗传学和电生理学方面对GRP系统在厌恶性情绪驱动的记忆、突触可塑性变化以及在中枢神经系统中的作用机制进行综述,希望为进一步明确GRP系统在中枢神经系统中的作用研究提供新的思路.     

Neuronal-glial remodeling: a structural basis for neuronal-glial interactions in the adult hypothalamus.

Increasing evidence is establishing that adult neurons and their associated glia can undergo state-dependent changes in their morphology and in consequence, in their relationships and functional interactions. A neuronal system that illustrates this kind of neuronal-glial plasticity in an exemplary fashion is that responsible for the secretion of the neurohormone oxytocin (OT). As shown by comparative ultrastructural analysis, during physiological conditions like lactation and dehydration, which result in enhanced peripheral and central release of the peptide, astrocytic coverage of OT neurons is markedly reduced and their surfaces are left directly juxtaposed. Such reduced glial coverage is of consequence to neuronal activity since it modifies extracellular ionic homeostasis and glutamate neurotransmission. In addition, it is probably prerequisite to the synaptic remodeling that occurs concurrently, and results in an enhanced number of inhibitory (GABAergic) and excitatory (glutamatergic, noradrenergic) synapses, thus further affecting neuronal function. The neuronal-glial and synaptic changes occur rapidly, within a matter of hours, and are reversible with termination of stimulation. The adult OT system retains many juvenile molecular features that may allow such plasticity, including expression of cell adhesion molecules implicated in neuronal-glial interactions during development, like polysialylated NCAM, F3/contactin and its ligand, the matrix glycoprotein, tenascin-C. On the other hand, OT itself can induce the changes since in vivo (ventricular microinfusion) or in vitro (on acute hypothalamic slices) application leads to glial and neuronal transformations similar to those induced by physiological stimuli.     

Astroglial cradle in the life of the synapse

Astroglial perisynaptic sheath covers the majority of synapses in the central nervous system. This glial coverage evolved as a part of the synaptic structure in which elements directly responsible for neurotransmission (exocytotic machinery and appropriate receptors) concentrate in neuronal membranes, whereas multiple molecules imperative for homeostatic maintenance of the synapse (transporters for neurotransmitters, ions, amino acids, etc.) are shifted to glial membranes that have substantially larger surface area. The astrocytic perisynaptic processes act as an ‘astroglial cradle’ essential for synaptogenesis, maturation, isolation and maintenance of synapses, representing the fundamental mechanism contributing to synaptic connectivity, synaptic plasticity and information processing in the nervous system.     

Synaptic plasticity in cephalopods; more than just learning and memory?

The outstanding behavioural capacity of cephalopods is underpinned by a highly sophisticated nervous system anatomy and neural mechanisms that often differ significantly from similarly complex systems in vertebrates and insects. Cephalopods exhibit considerable behavioural flexibility and adaptability, and it might be expected that this should be supported by evident cellular and synaptic plasticity. Here, we review what little is known of the cellular mechanisms that underlie plasticity in cephalopods, particularly from the point of view of synaptic function. We conclude that cephalopods utilise short-, medium-, and long-term plasticity mechanisms that are superficially similar to those so far described in vertebrate and insect synapses. These mechanisms, however, often differ significantly from those in other animals at the biophysical level and are deployed not just in the central nervous system, but also to a limited extent in the peripheral nervous system and neuromuscular junctions.     

代谢型谷氨酸受体在突触可塑性中的作用

突触可塑性是近几年神经科学研究的热点之一,因为它对于理解神经系统的学习、学习和记忆、多咱神经疾病等许多过程有着重要的意义。除了离子型谷氨酸受体外,代谢型谷氨酸受体也参与了一些脑区中不同形式的突触可塑性变化。本文就代谢型谷氨酸受体选择性激动剂和拮抗剂对长时程增强和长时程抑制的作用进行了综述,以助于人们进一步理解突触可塑性的细胞和分子机制。     

Long-term potentiation and olfactory memory formation in the carp (<Emphasis Type="Italic">Cyprinus carpio</Emphasis> L.) olfactory bulb

Long-term potentiation of synaptic transmission is considered to be an elementary process underlying the cellular mechanism of memory formation. In the present study we aimed to examine whether or not the dendrodendritic mitral-to-granule cell synapses in the carp olfactory bulb show plastic changes after their repeated activation. It was found that: (1) the dendrodendritic mitral-to-granule cell synapses showed three types of plasticity after tetanic electrical stimulation applied to the olfactory tract—long-term potentiation (potentiation lasting >1 h), short-term potentiation (potentiation lasting <1 h) and post-tetanic potentiation (potentiation lasting <10 min); (2) Long-term potentiation was generally induced when both the dendrodendritic mitral-to-granule cell synapses and centrifugal fiber-to-granule cell synapses were repeatedly and simultaneously activated; (3) long-term enhancement (>1 h) of the odor-evoked bulbar response accompanied the electrically-induced LTP, and; (4) repeated olfactory stimulation enhanced dendrodendritic mitral-to-granule cell transmission. Based on these results, it was proposed that long-term potentiation (as well as olfactory memory) occurs at the dendrodendritic mitral-to-granule cell synapses after strong and long-lasting depolarization of granule cells, which follows repeated and simultaneous synaptic activation of both the peripheral and deep dendrites (or somata).     

Neuronal, glial and synaptic remodeling in the adult hypothalamus: functional consequences and role of cell surface and extracellular matrix adhesion molecules

The adult hypothalamo-neurohypophysial system (HNS) undergoes activity-dependent morphological plasticity which modifies astrocytic coverage of its oxytocinergic neurons and their synaptic inputs. Thus, during physiological conditions that enhance central and peripheral release of oxytocin (OT), adjacent somata and dendrites of OT neurons become extensively juxtaposed, without intervening astrocytic processes and receive an increased number of synapses. The morphological changes occur within a few hours and are reversible with termination of stimulation. The reduced astrocytic coverage has direct functional consequences since it modifies extracellular ionic homeostasis, synaptic transmission, and the size and geometry of the extracellular space. It also contributes indirectly to neuronal function by permitting formation of synapses on neuronal surfaces freed of astrocytic processes. Overall, such remodeling is expected to potentiate activated neuronal firing, especially in clusters of tightly packed neurons, an anatomical arrangement characterizing OT neurons. This plasticity connotes dynamic cell interactions that must bring into play cell surface and extracellular matrix adhesive proteins like those intervening in developing neuronal systems undergoing neuronal-glial and synaptogenic transformations. It is worth noting, therefore, that adult HNS neurons and glia continue to express such molecules, including polysialic acid (PSA)-enriched neural cell adhesion molecule (PSA-NCAM) and the glycoprotein, tenascin-C. PSA is a large, complex sugar on the extracellular domain of NCAM considered a negative regulator of adhesion; it occurs in large amounts on the surfaces of HNS neurons and astrocytes. Tenascin-C, on the other hand, possesses adhesive and repulsive properties; it is secreted by HNS astrocytes and occurs in extracellular spaces and on cell surfaces after interaction with appropriate ligands. These molecules have been considered permissive factors for morphological plasticity. However, because of their localization and inherent properties, they may also serve to modulate the extracellular environment and in consequence, synaptic and volume transmission in a system in which the extracellular compartment is constantly being modified.     

Transmission,Development, and Plasticity of Synapses

Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre- and postsynaptic cells communicate to regulate plasticity in response to activity.     

Exercise-dependent regulation of glial cell line-derived neurotrophic factor (GDNF) expression in skeletal muscle and its importance for the neuromuscular system

The focus of this review is to highlight the importance of glial cell line-derived neurotrophic factor (GDNF) for the motor nervous system. GDNF is the most potent survival factor for motor neurons, where it enhances maintenance and survival of both developing and mature motor neurons in vivo and in vitro. GDNF aids in neuromuscular junction formation, maintenance, and plasticity, where skeletal muscle-derived GDNF may be responsible for this phenomenon. Increased levels of physical activity can increase GDNF protein levels in skeletal muscle, where alterations in acetylcholine and acetylcholine receptor activation may be involved in regulation of these changes observed. With inactivity and disuse, GDNF expression shows different patterns of regulation in the central and peripheral nervous systems. Due to its potent effects for motor neurons, GDNF is being extensively studied in neuromuscular diseases.     

Plasticity of dendritic function

The various properties of neuronal dendrites--their morphology, active membrane and synaptic properties--all play important roles in determining the functional capabilities of central nervous system neurons. Because of their fundamental involvement in both synaptic integration and synaptic plasticity, the active dendritic properties are important for both neuronal information processing and storage. The active properties of dendrites are determined by the densities of voltage-gated ion channels located within the dendrites in addition to the biophysical characteristics of those channels. The real power of this system resides in the level of plasticity that is provided by the many forms of channel modulation known to exist in neurons. Indeed, voltage gated ion channel modulation shapes the active properties of neuronal dendrites to specific conditions, thus tailoring the functional role of the single neuron within its circuit.     

Mechanisms of axon regeneration: The significance of proteoglycans

BackgroundTherapeutics specific to neural injury have long been anticipated but remain unavailable. Axons in the central nervous system do not readily regenerate after injury, leading to dysfunction of the nervous system. This failure of regeneration is due to both the low intrinsic capacity of axons for regeneration and the various inhibitors emerging upon injury. After many years of concerted efforts, however, these hurdles to axon regeneration have been partially overcome.Scope of reviewThis review summarizes the mechanisms regulating axon regeneration. We highlight proteoglycans, particularly because it has become increasingly clear that these proteins serve as critical regulators for axon regeneration.Major conclusionsStudies on proteoglycans have revealed that glycans not only assist in the modulation of protein functions but also act as main players—e.g., as functional ligands mediating intracellular signaling through specific receptors on the cell surface. By regulating clustering of the receptors, glycans in the proteoglycan moiety, i.e., glycosaminoglycans, promote or inhibit axon regeneration. In addition, proteoglycans are involved in various types of neural plasticity, ranging from synaptic plasticity to experience-dependent plasticity.General significanceAlthough studies on proteins have progressively facilitated our understanding of the nervous system, glycans constitute a new frontier for further research and development in this field. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.     

The neuropoietic cytokine family in development, plasticity, disease and injury

Neuropoietic cytokines are well known for their role in the control of neuronal, glial and immune responses to injury or disease. Since this discovery, it has emerged that several of these proteins are also involved in nervous system development, in particular in the regulation of neurogenesis and stem cell fate. Recent data indicate that these proteins have yet more functions, as key modulators of synaptic plasticity and of various behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of psychiatric disorders.