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. While the mechanism of action of this complex sugar is unknown, it is now clear that it is a necessary molecular component of various cell transformations, including those responsible for activity-dependent synaptic remodeling.Key words: adhesion, synaptic plasticity, astrocytes, central nervous system, hypothalamus, olfactory system     

Stress and Plasticity in the Limbic System

The adult nervous system is not static, but instead can change, can be reshaped by experience. Such plasticity has been demonstrated from the most reductive to the most integrated levels, and understanding the bases of this plasticity is a major challenge. It is apparent that stress can alter plasticity in the nervous system, particularly in the limbic system. This paper reviews that subject, concentrating on: a) the ability of severe and/or prolonged stress to impair hippocampal-dependent explicit learning and the plasticity that underlies it; b) the ability of mild and transient stress to facilitate such plasticity; c) the ability of a range of stressors to enhance implicit fear conditioning, and to enhance the amygdaloid plasticity that underlies it.     

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.     

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.     

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．     

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.     

Learning in sensorimotor circuits

The study of plasticity in the central nervous system is a major and very dynamic neuroscience research field with enormous clinical potential. Considerable advances in this field have been made during the past 10 years. It now appears that most circuits in the brain and spinal cord show plasticity and that they can be modified by experience. Knowledge of the mechanisms of plasticity in the nervous system is therefore essential for the understanding of how the nervous system is wired during development and how it adapts in response to changes in the body and environment. Recent findings indicate that functional sensorimotor modules probe the sensory signals from the body that are generated as a consequence of module specific activity and use this sensory feedback to calibrate the strength in its input-output connections. This experience-dependent signal adapts the circuitry in the sensorimotor module to the body anatomy and biomechanics.     

Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system

The adult nervous system is plastic, allowing us to learn, remember, and forget. Experience-dependent plasticity occurs at synapses--the specialized points of contact between neurons where signaling occurs. However, the mechanisms that regulate the strength of synaptic signaling are not well understood. Here, we define a Wnt-signaling pathway that modifies synaptic strength in the adult nervous system by regulating the translocation of one class of acetylcholine receptors (AChRs) to synapses. In Caenorhabditis elegans, we show that mutations in CWN-2 (Wnt ligand), LIN-17 (Frizzled), CAM-1 (Ror receptor tyrosine kinase), or the downstream effector DSH-1 (disheveled) result in similar subsynaptic accumulations of ACR-16/α7 AChRs, a consequent reduction in synaptic current, and predictable behavioral defects. Photoconversion experiments revealed defective translocation of ACR-16/α7 to synapses in Wnt-signaling mutants. Using optogenetic nerve stimulation, we demonstrate activity-dependent synaptic plasticity and its dependence on ACR-16/α7 translocation mediated by Wnt signaling via LIN-17/CAM-1 heteromeric receptors.     

Matrix metalloproteinases and their inhibitors,modulators of neuro-immune interactions and of pathophysiological processes in the nervous system

The matrix metalloproteinases (MMPs) belong to a growing family of Zn2+-dependent endopeptidases, secreted or membrane-bound (MT-MMP), that regulate or degrade by proteolytic cleavage protein components of the extracellular matrix, cytokines, chemokines, cell adhesion molecules and a variety of membrane receptors. MMP activity is counterbalanced by their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), a family of 4 secreted multifunctional proteins that have growth promoting activities. In physiological conditions MMP activity is tightly regulated and altered MMP regulation is associated with pathological processes including inflammation, cell proliferation, cell death and tissue remodeling. The MMP/TIMP system is involved in the development and function of cells of the immune system by promoting their differentiation, activation, migration across basement membranes and tissues. In the last years, data has accumulated indicating that the MMP/TIMP system is expressed in the nervous system where it regulates neuro-immune interactions and plays a major role in pathophysiological processes. In this review, we present recent in vivo and in vitro studies that highlight the contribution of the MMP/TIMP system to various diseases of the nervous system, involving blood brain barrier breakdown, neuroinflammation, glial reactivity, neuronal death, reactive plasticity, and to developmental and physiological processes including cell migration, axonal sprouting and neuronal plasticity. This review also alludes to the beneficial effects of synthetic MMP inhibitors in different animal models of neuropathology. In all, a further understanding of the role of MMPs and TIMPs in the nervous system should contribute to unravel mechanisms of neuronal plasticity and pathology and set the basis of new therapeutic strategies in nervous system disorders based on the development of synthetic MMP inhibitors.     

Estrogen receptor immunoreactivity in Schwann-like brain macroglia.

Olfactory ensheathing cells, tanycytes, pituicytes, pineal glia, retinal Müller cells, and Bergmann glia of normal male rats express concomitantly estrogen receptor, low-affinity neurotrophin receptor, antigen O4, and GFAP, markers characteristic of nonmyelinating Schwann cells. These cells were able to survive and proliferate when cultured from adult tissue, promoted neurite outgrowth, and could guide and ensheath growing neurites. We called this distinct group of growth-promoting central nervous system (CNS) macroglia aldynoglia (Greek: to make grow). Its proliferative and growth-promoting properties seem to be retained during the whole lifetime of the organism in those CNS loci where normal function depends on continuous axon renewal. Aldynoglia plasticity seems totally or partially lost with age where and when it is no longer critical, as in the case of adult cortical and spinal cord radial glia. The concomitant expression of estrogen receptor and low-affinity neurotrophin receptor may promote Schwann-like plasticity of glial cells.     

New concepts on the structure of the neuronal networks: The miniaturization and hierarchical organization of the central nervous system

The hypothesis is introduced that miniaturization of neuronal circuits in the central nervous system and the hierarchical organization of the various levels, where information handling can take place, may be the key to understand the enormous capability of the human brain to store engrams as well as its astonishing capacity to reconstruct and organize engrams and thus to perform highly sophisticated integrations. The concept is also proposed that in order to understand the relationship between the structural and functional plasticity of the central nervous system it is necessary to postulate the existence of memory storage at the network level, at the local circuit level, at the synaptic level, at the membrane level, and finally at the moIecular level. Thus, memory organization is similar to the hierarchical organization of the various levels, where information handling takes place in the nervous system. In addition, each higher level plays a role in the reconstruction and organization of the engrams stored at lower levels. Thus, the trace of the functionally stored memory (i.e. its reconstruction and organization at various levels of storage) will depend not only on the chemicophysical changes in the membranes of the local circuits but also on the organization of the local circuits themselves and their associated neuronal networks.Dedicated to Prof. R. Luft for his outstanding achievements in endocrinology and his provocative and inspiring discussions in biology.     

Neuronal cytoskeleton in synaptic plasticity and regeneration

During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo‐dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre‐ and post‐synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system.     

Stem cell dogmas in the genomics era

Recently, much excitement has been generated by strong suggestions that stem cells isolated from diverse somatic tissues may have a previously unsuspected degree of developmental or differentiation plasticity. For example, a hematopoietic stem cell may be capable of producing mature liver cells, muscle tissue or even neurons. Similarly, central nervous system stem cells or muscle stem cells may be capable of producing mature blood cell populations. These observations have called into question several fundamental dogmas of developmental biology. In addition, these observations offer extraordinary promise in the clinical setting. It is of paramount importance to rigorously assess the suggested plasticity phenomena using precise clonal analysis. In order to explore the plasticity phenomena in more direct ways, it is necessary to develop in vitro systems where such behavior can be recapitulated in a well-defined setting. Finally, stem cell plasticity will be governed, at least in part, by cell-autonomous mechanisms: that is, those mediated by the panel of gene products expressed in stem cells. Therefore, it is necessary to identify the complete gene expression profile that defines the stem cell.     

Mitochondrial Regulation of Neuronal Plasticity

The structure and function of neurons is dynamic during development and in adaptive responses of the adult nervous system to environmental demands. The mechanisms that regulate neuronal plasticity are poorly understood, but are believed to involve neurotransmitter and neurotrophic factor signaling pathways. In the present article, I review emerging evidence that mitochondria play important roles in regulating developmental and adult neuroplasticity. In neurons, mitochondria are located in axons, dendrites, growth cones and pre- and post-synaptic terminals where their movements and functions are regulated by local signals such as neurotrophic factors and calcium influx. Mitochondria play important roles in fundamental developmental processes including the establishment of axonal polarity and the regulation of neurite outgrowth, and are also involved in synaptic plasticity in the mature nervous system. Abnormalities in mitochondria are associated with neurodegenerative and psychiatric disorders, suggesting a therapeutic potential for approaches that target mitochondrial mechanisms. Special issue dedicated to John P. Blass.     

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.     

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.     

Semaphorin-neuropilin-1 interactions in plasticity and regeneration of adult neurons

During development, axonal growth cones are guided to their appropriate targets by many attractive and repulsive cues. It has become increasingly clear over the last few years that how the growth cone responds to these cues depends both on the molecular nature of the cue and on the internal state of the neuron. The unexpected result is that the same molecule can act as an attractor or as a repellent. A number of guidance cues used by neurons during development are retained in the adult nervous system, where their function is often still unclear. Most of these molecules are implicated in plasticity in the adult nervous system and can play a role (sometimes maladaptive) in neuronal regeneration after injury. A group of axonal guidance cues that has been well studied in development is the semaphorin family of secreted and membrane-anchored proteins, which has been implicated in axon steering, fasciculation, branching and synapse formation. This review focuses on semaphorin-3A (probably the best-characterized semaphorin) and its receptors (in particular neuropilin-1) in the adult nervous system and argues that semaphorin-3A plays a role in the maintenance and regeneration of adult sensory neurons.