The dual role of the extracellular matrix in synaptic plasticity and homeostasis

Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health.     

Brain circuitry outside the synaptic cleft

A growing body of experimental evidence suggests that astroglia, and possibly microglia, play an important part in regulating synaptic networking of the brain. It has also emerged that extracellular matrix (ECM) structures that enwrap synaptic connections can generate molecular signals affecting both neuronal and glial activity. Thus it appears that the mechanism of information processing in the brain, which has hitherto been associated almost exclusively with neural circuits, could also involve informative signal exchange outside the synaptic cleft. In this Theme Issue, research teams including leading experts on astroglia–neuron communication and on ECM signalling report their recent findings, share their views and discuss future conceptual advances in the field. Potential implications for drug development and new therapeutic targets with regard to some common neurological conditions are discussed throughout the issue.     

Extracellular matrix functions during neuronal migration and lamination in the mammalian central nervous system

Extracellular matrix (ECM) glycoproteins are expressed in the central nervous system (CNS) in complex and developmentally regulated patterns. The ECM provides a number of critical functions in the CNS, contributing both to the overall structural organization of the CNS and to control of individual cells. At the cellular level, the ECM affects its functions by a wide range of mechanisms, including providing structural support to cells, regulating the activity of second messenger systems, and controlling the distribution and local concentration of growth and differentiation factors. Perhaps the most well known role of the ECM is as a substrate on which motile cells can migrate. Genetic, cell biological, and biochemical studies provide strong evidence that ECM glycoproteins such as laminins, tenascins, and proteoglycans control neuronal migration and positioning in several regions of the developing and adult brain. Recent findings have also shed important new insights into the cellular and molecular mechanisms by which reelin regulates migration. Here we will summarize these findings, emphasizing the emerging concept that ECM glycoproteins promote different modes of neuronal migration such as radial, tangential, and chain migration. We also discuss several studies demonstrating that mutations in ECM glycoproteins can alter neuronal positioning by cell nonautonomous mechanisms that secondarily affect migrating neurons.     

Glial cell development and function in the Drosophila visual system

In the developing nervous system, building a functional neuronal network relies on coordinating the formation, specification and survival to diverse neuronal and glial cell subtypes. The establishment of neuronal connections further depends on sequential neuron-neuron and neuron-glia interactions that regulate cell-migration patterns and axon guidance. The visual system of Drosophila has a highly regular, retinotopic organization into reiterated interconnected synaptic circuits. It is therefore an excellent invertebrate model to investigate basic cellular strategies and molecular determinants regulating the different developmental processes that lead to network formation. Studies in the visual system have provided important insights into the mechanisms by which photoreceptor axons connect with their synaptic partners within the optic lobe. In this review, we highlight that this system is also well suited for uncovering general principles that underlie glial cell biology. We describe the glial cell subtypes in the visual system and discuss recent findings about their development and migration. Finally, we outline the pivotal roles of glial cells in mediating neural circuit assembly, boundary formation, neural proliferation and survival, as well as synaptic function.     

Making memories last: the synaptic tagging and capture hypothesis

The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.     

Casting a net on dendritic spines: the extracellular matrix and its receptors

Dendritic spines are dynamic structures that accommodate the majority of excitatory synapses in the brain and are influenced by extracellular signals from presynaptic neurons, glial cells, and the extracellular matrix (ECM). The ECM surrounds dendritic spines and extends into the synaptic cleft, maintaining synapse integrity as well as mediating trans-synaptic communications between neurons. Several scaffolding proteins and glycans that compose the ECM form a lattice-like network, which serves as an attractive ground for various secreted glycoproteins, lectins, growth factors, and enzymes. ECM components can control dendritic spines through the interactions with their specific receptors or by influencing the functions of other synaptic proteins. In this review, we focus on ECM components and their receptors that regulate dendritic spine development and plasticity in the normal and diseased brain.     

Modern Concepts of Cholinergic Neurotransmission at the Motor Synapse

Cholinergic synaptic contact between motor neuron and skeletal muscle fiber is perhaps one of the core objects for investigations of molecular mechanisms underlying the communication between neurons and innervated cells. In the studies conducted on this object in the past few decades, a large amount of experimental data was obtained that substantially complemented a traditional view on synaptic transmission. In particular, it was established that (i) acetylcholine is released from the nerve ending in both quantal and nonquantal ways; (ii) molecular mechanisms of the processes of the quantal acetylcholine release—spontaneous and evoked by electrical stimuli—have unique features and can be regulated independently; (iii) acetylcholine release from the nerve ending is accompanied by a release of a number of synaptically active molecules modulating the processes of secretion or reception of the main mediator; (iv) signal molecules affecting the process of cholinergic neurotransmission can be released not only from the nerve ending but also from glial cells and muscle fiber; (v) molecular mechanisms of the regulation of synaptic transmission are highly diverse and go beyond the alteration of the number of the released acetylcholine quanta. Thus, the neuromuscular junction shall be deemed currently as complicated and adaptive synapse characterized by a wide range of multiloop intercellular signaling pathways between presynaptic motor neuron ending, muscle fiber, and glial cells ensuring a high safety factor of synaptic transmission and the possibility of its fine tuning.     

Role of glia in synapse development

Recent studies suggest that glial cells regulate certain aspects of synapse development. Neurons can form synapses without glia, but may require glia-derived cholesterol to form numerous and efficient synapses. During synapse maturation, soluble and contact-dependent factors from glia may influence the composition of the postsynaptic density. Finally, synaptic connections appear to require glia to support their structural stability. Given the new evidence, it may be time now to acknowledge glia as a source for synaptogenesis-promoting signals. Scrutinizing the molecular mechanisms underlying this new function of glia and testing its relevance in vivo may help to understand how synapses develop and why they degenerate under pathological conditions.     

Glial responses to steroids as markers of brain aging.

Glia mediate neuroendocrine and neuroimmune functions that are altered during the process of normal aging. The biological functions of glia are also important in synaptic remodeling and the loss of synaptic connections that occur during aging. These functions are carried out by changes in glia, including changes in shape, interactions with neurons and other glia, and gene expression. The predominant change that occurs in glia during aging is glial activation, which can progress to reactive gliosis in response to neurodegeneration. More markers are needed to distinguish normal and reactive glia. During aging, astrocytes hypertrophy and exhibit signs of metabolic activation, and astrocytic processes surround neurons. Microglia also become activated and subsets of activated microglial increase in number and may enter the phagocytic or reactive stage. Glial markers of brain aging and glial activation include glial fibrillary acidic protein (GFAP) and transforming growth factor (TGF)-beta1, which are increased in astrocytes and microglia, respectively. Steroids regulate the interactions between glia and neurons and glial gene expression, including GFAP and TGF-beta1. Therefore, changes in these parameters during aging may be due to altered steroid regulation. In general, the effects of steroids oppose the effects of aging. Recent data indicate that steroid treatment can decrease the expression of GFAP in the aged brain, yet GFAP is resistant to down-regulation by endogenous glucocorticoids. Cellular and molecular markers of glial activation are being used to determine how changes in neuroendocrine and neuroimmune regulation contribute to repair and functional recovery that may reverse synaptic loss and cognitive impairment during aging.     

A homeostatic model of neuronal firing governed by feedback signals from the extracellular matrix

Molecules of the extracellular matrix (ECM) can modulate the efficacy of synaptic transmission and neuronal excitability. These mechanisms are crucial for the homeostatic regulation of neuronal firing over extended timescales. In this study, we introduce a simple mathematical model of neuronal spiking balanced by the influence of the ECM. We consider a neuron receiving random synaptic input in the form of Poisson spike trains and the ECM, which is modeled by a phenomenological variable involved in two feedback mechanisms. One feedback mechanism scales the values of the input synaptic conductance to compensate for changes in firing rate. The second feedback accounts for slow fluctuations of the excitation threshold and depends on the ECM concentration. We show that the ECM-mediated feedback acts as a robust mechanism to provide a homeostatic adjustment of the average firing rate. Interestingly, the activation of feedback mechanisms may lead to a bistability in which two different stable levels of average firing rates can coexist in a spiking network. We discuss the mechanisms of the bistability and how they may be related to memory function.     

The role of perisynaptic glial sheaths in glutamate spillover and extracellular Ca(2+) depletion

Recent findings suggest that rapid activation of extrasynaptic receptors and transient depletion of extracellular Ca(2+) may represent an important component of glutamatergic synaptic transmission. These phenomena imply a previously unrecognized role for synaptic glial sheaths: to retard extracellular diffusion in the synaptic vicinity. The present study is an attempt to assess the extent and physiological implications of this retardation using a detailed compartmental model of the typical synaptic environment. The model allows reconstruction of a partial (asymmetric) glial sheath covered with transporter molecules, which gives a more realistic representation of the vicinity of central synapses. Simulations show to what extent, in conditions compatible with physiology, the occupancy of synaptic receptors and the depletion of Ca(2+) in the cleft increase with increased glial coverage. The impact of glial sheaths on synaptic transmission is shown to become greater with smaller synapses and with slower kinetics of perisynaptic ion transients. At a calyceal synapse, a profound temporal filtering of fast Ca(2+) influx is found, and similar phenomena are predicted to occur following simultaneous activation of multiple synapses in the neuropil. The results provide a quantitative guidance for interpretation of physiological experiments that address fast transients of neurotransmitters and small ions in the brain tissue.     

Astrocyte-dependent circuit remodeling by synapse phagocytosis

In the central nervous system, synaptic pruning, the removal of unnecessary synaptic contacts, is an essential process for proper circuit maturation in neurodevelopment as well as for synaptic homeostasis in the adult stage. Dysregulation of synaptic pruning can contribute to the initiation and progression of various mental disorders, such as schizophrenia and depression, as well as neurodegenerative diseases including Alzheimer's disease. In the past 15 years, pioneering works have demonstrated that different types of glial cells regulate the number of synapses by selectively eliminating them through phagocytic molecular machinery. Although a majority of findings have been focused on microglia, it is increasingly evident that astrocytes function as a critical player in activity-dependent synapse elimination in developing, adult, and diseased brains. In this review, we will discuss recent findings showing the mechanisms and physiological importance of astrocyte-mediated synapse elimination in controlling synapses and circuit homeostasis. We propose that astrocytes play dominant and non-redundant roles in eliminating synapses during the activity-dependent circuit remodeling processes that do not involve neuro-inflammation.     

A dialogue between glia and neurons in the retina: modulation of neuronal excitability

Bidirectional signaling between neurons and glial cells has been demonstrated in brain slices and is believed to mediate glial modulation of synaptic transmission in the CNS. Our laboratory has characterized similar neuron-glia signaling in the mammalian retina. We find that light-evoked neuronal activity elicits Ca(2+) increases in Müller cells, which are specialized retinal glial cells. Neuron to glia signaling is likely mediated by the release of ATP from neurons and is potentiated by adenosine. Glia to neuron signaling has also been observed and is mediated by several mechanisms. Stimulation of glial cells can result in either facilitation or depression of synaptic transmission. Release of D-serine from Müller cells might also potentiate NMDA receptor transmission. Müller cells directly inhibit ganglion cells by releasing ATP, which, following hydrolysis to adenosine, activates neuronal A(1) receptors. The existence of bidirectional signaling mechanisms indicates that glial cells participate in information processing in the retina.     

神经胶质细胞与突触可塑性研究新进展

突触的可塑性是研究学习与记忆的基础,很长时间以来人们对突触的可塑性研究主要集中在神经元和突触上;而胶质细胞的作用较少受到注意。最近的研究发现胶质细胞也参与突触的构成并影响突触的活动。研究表明中枢神经系统中的胶质细胞包括星形胶质细胞、小胶质细胞和少突胶质细胞可分别通过谷氨酸、丝氨酸、甘氨酸、ATP等信号调节突触的可塑性,从而为突触的可塑性研究提供了新的思路和方向,并有助于阐明突触的发生以及学习与记忆的机制。     

The role of glial cells in synapse elimination

Excessive synapses generated during early development are eliminated extensively to form functionally mature neural circuits. Synapses in juvenile and mature brains are highly dynamic, and undergo remodeling processes through constant formation and elimination of dendritic spines. Although neural activity has been implicated in initiating the synapse elimination process cell-autonomously, the cellular and molecular mechanisms that transduce changes in correlated neural activity into structural changes in synapses are largely unknown. Recently, however, new findings provide evidence that in different species, glial cells, non-neuronal cell types in the nervous system are crucial in eliminating neural debris and unwanted synapses through phagocytosis. Glial cells not only clear fragmented axons and synaptic debris produced during synapse elimination, but also engulf unwanted synapses thereby actively promoting synapse elimination non-cell autonomously. These new findings support the important role of glial cells in the formation and maintenance of functional neural circuits in development as well as in adult stages and neurodegenerative diseases.     

Gliotransmission at central glutamatergic synapses: D-serine on stage.

Long ignored and only considered as housekeeping cells for neurons, astroglial cells in the last decade have gained increasing attention as key players of higher functions in healthy brain, but also in diseases. This revolution in our way to think the active brain culminates in the concept of a tripartite synapse, which considers glial cells and notably astrocytes as an integral dynamic partner of synapses. Glia not only listens but also talks to neurons through the release of neuroactive substances. Recently much attention has been paid to the role played by the atypical amino acid D-serine in this signalling pathway. This molecule synthesized through racemization of L-serine fulfils most criteria as a gliotransmitter and as the endogenous ligand for the strychnine-insensitive glycine binding site of the NMDA receptors. D-serine is considered to be a permissive factor for long-term changes in synaptic plasticity and neuronal migration through activation of NMDA receptors. It is also known that disturbance of NMDA receptors activity can cause cell death. Not surprisingly, then, D-serine has also been found to promote neurons death in experimental models of beta-amyloid peptide-induced neuroinflammation and of ischaemia by overactivating the NMDA receptors. Finally, in a more recent past, studies have pointed to the molecular mechanisms leading to D-serine release into and removal from the synaptic cleft.     

Extracellular Matrix in Neural Plasticity and Regeneration

The extracellular matrix (ECM) is a fundamental component of biological tissues. The ECM in the central nervous system (CNS) is unique in both composition and function. Functions such as learning, memory, synaptogenesis, and plasticity are regulated by numerous ECM molecules. The neural ECM acts as a non-specific physical barrier that modulates neuronal plasticity and axon regeneration. There are two specialized types of ECM in the CNS, diffuse perisynaptic ECM and condensed ECM, which selectively surround the perikaryon and initial part of dendritic trees in subtypes of neurons, forming perineuronal nets. This review presents the current knowledge about the role of important neuronal ECM molecules in maintaining the basic functions of a neuron, including electrogenesis and the ability to form neural circuits. The review mainly focuses on the role of ECM components that participate in the control of key events such as cell survival, axonal growth, and synaptic remodeling. Particular attention is drawn to the numerous molecular partners of the main ECM components. These regulatory molecules are integrated into the cell membrane or disposed into the matrix itself in solid or soluble form. The interaction of the main matrix components with molecular partners seems essential in molecular mechanisms controlling neuronal functions. Special attention is paid to the chondroitin sulfate proteoglycan 4, type 1 transmembrane protein, neural-glial antigen 2 (NG2/CSPG4), whose cleaved extracellular domain is such a molecular partner that it not only acts directly on neural and vascular cells, but also exerts its influence indirectly by binding to resident ECM molecules.

     

Cerebellar Bergmann glia: an important model to study neuron-glia interactions

The biochemical effects triggered by the action of glutamate, the main excitatory amino acid, on a specialized type of glia cells, Bergmann glial cells of the cerebellum, are a model system with which to study glia-neuronal interactions. Neuron to Bergmann glia signaling is involved in early stages of development, mainly in cell migration and synaptogenesis. Later, in adulthood, these cells have an important role in the maintenance and proper function of the synapses that they surround. Major molecular targets of this cellular interplay are glial glutamate receptors and transporters, both of which sense synaptic activity. Glutamate receptors trigger a complex network of signaling cascades that involve Ca(2+) influx and lead to a differential gene-expression pattern. In contrast, Bergmann glia glutamate transporters participate in the removal of the neurotransmitter from the synaptic cleft and act also as signal transducers that regulate, in the short term, their own activity. These exciting findings strengthen the concept of active participation of glial cells in synaptic transmission and the involvement of neuron-glia circuits in the processing of brain information.