Preface

Alexander Dityatev, Magdeburg, Germany

Bernhard Wehrle-Haller, Geneva, Switzerland

Asla Pitkänen, Kuopio, Finland

The organization of the extracellular matrix (ECM) is a reflection of the role and function of organs in our bodies. The interaction of cells with the ECM determines their polarity, shape, and form and is providing cues for survival and proliferation. The brain, in comparison with other organs, shows an extremely complex architecture, in which neurons, glial cells, and blood vessels are interacting to create and maintain a dynamic network, in which beneficial synaptic connections need to be actively maintained and other remodeled in response to changes in signaling input. Similar to other organ systems, cell-cell interactions based on direct contacts via cadherins and signaling receptors, as well as cell-matrix interactions with the ECM scaffold, are controlling the organization of glial cells and neurons as well as the projections of neurites and location of synapses. All these structures are embedded within an ECM scaffold formed by fiber or network-forming proteins and membrane-anchored or secreted glycosaminoglycans.

Despite recent advances in the ECM field, the importance of neural ECM for physiological and pathological processes is less widely recognized than that of other nervous system elements. To overcome this, a European consortium "Brain Extracellular Matrix in Health and Disease (ECMNet)" was established in 2010 as a part of intergovernmental framework for European Cooperation in Science and Technology (COST). Now, ECMNet combines more than 200 young and established researchers from 20 European countries (http://www.costbm1001.eu/). Each book chapter of this volume is prepared involving ECMNet members and other leading experts from the USA and Japan. The chapters cover the broad range of topics, grouped into four parts, which are devoted to normal physiological functions of neural ECM, its role in brain diseases, development of methods to image the ECM, to therapeutically target it, and to generate artificial ECM.

Functions of Neural ECM

The neural ECM is well recognized to play a key role in neural development and the first two chapters of the book are devoted to this topic. Theocharidis, Long, ffrench-Constant, and Faissner (2014) discuss available data on expression of tenascins, laminins, and proteoglycans in the ECM of the stem cell niche and argue for crucial importance of ECM for the biology of this cellular compartment. Heikkinen, Pihlajaniemi, Faissner, and Yuzaki (2014) focus on how proteoglycans, tenascin, and C1q (C1qDC) family proteins regulate synapse formation, maintenance, and pruning during neural development. In the adult central nervous system (CNS), multiple neural ECM molecules together with astroglial, pre-, and postsynaptic elements form tetrapartite synapses, and the ECM regulates Hebbian synaptic plasticity through the modulation of perisomatic GABAergic inhibition, intrinsic neuronal excitability, and intracellular signaling, as presented by Senkov, Andjus, Radenovic, Soriano, and Dityatev (2014). This chapter also gives an account on bidirectional modulation of memory acquisition by ECM molecules and highlights that removal of ECM may promote cognitive flexibility and extinction of fear and drug memoriesTo stabilize network dynamics and avoid hypo- and hyperexcitability of neurons, adaptive Hebbian modifications of neurons and synapses must be complemented by homeostatic forms of plasticity. Frischknecht, Chang, Rasband, and Seidenbecher (2014) point to the ECM as a prime candidate to orchestrate and integrate individual cellular states into the homeostasis of the tissue, which is implemented via synaptic scaling, adjustment in the balance between excitation and inhibition, and axon initial segment plasticity. Many effects of ECM molecules are mediated by their interactions with cognate ECM receptors, first of all, integrins. Kerrisk, Cingolani, and Koleske (2014) discuss how activation of ECM receptors modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. Tsilibary and colleagues (2014) focus on the role of extracellular proteolysis and put forward a challenging view that the main function of proteolysis is not the degradation of ECM and the loosening of perisynaptic structures, but rather a release of signaling molecules from the ECM, transsynaptic proteins, and latent forms of growth factors.

Neural ECM in Brain Diseases

As summarized in the first part of this volume, various components of the ECM play a significant role in maintenance of the environmental milieu for different cell types in the CNS and in regulation of cellular responses to physiological stimuli. Compelling evidence collected over recent years, however, demonstrate that plasticity in the ECM can also be triggered by genetic or acquired pathological stimuli to the brain. Moreover, the ECM is an active player in the CNS repair process by forming a scaffold, which orchestrates the cellular plasticity events toward either favorable or unfavorable outcome over the lifespan. Milosevic, Judas, Aronica, and Kostovic (2014) discuss the expression pattern of major components of the fetal ECM in the human brain and the role they play during normal laminar and connectivity development as well as in the neurodevelopmental disorders. Kwok, Yang, and Fawcett (2014) address current progresses of chondroitin sulfate proteoglycans in regulating plasticity in neurodegenerative diseases, brain tumors, and CNS injury. They also investigate the opportunities of manipulating ECM to facilitate postinjury recovery. Vandooren, Damme, and Ghislain Opdenakker (2014) discuss the mechanisms of matrix metalloproteinase MMP-9 in neuroinflammation, and the use of MMP-9-specific inhibitors as anti-inflammatory agents. Morawski, Filippov, Tzinia, Tsilibary, and Vargova (2014) review the information on age-related changes in the ECM, how they could contribute to pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, and what could be the therapeutic approaches targeted to the ECM to combat, for example, amyloid clearance. Pitkänen et al. (2014) review the role of uPAR-interactome, MMPs and TIMPs, tenascin-R, and LG1 in different epilepsy syndromes and how they contribute to epileptogenesis and ictogenesis. In addition, the role of the ECM in epilepsy-related comorbidies and the current status of in vivo imaging of ECM-related molecules in patients are discussed. Lubbers, Smit, Spijker, and van den Oever (2014) review neurodevelopmental and other mechanisms affecting different components of the ECM, which could lead to the expression of neuropsychiatric disorders, in particular, addiction, schizophrenia, and mood disorders.

Neural ECM-Targeting Tools and Therapeutics

There is a growing interest to develop methodology allowing for detailed structural and functional analysis of ECM, particularly in vivo, to be able to follow ECM remodeling during plasticity and in diseased brains. Zeug et al. (2014) provide a detailed overview of current microscopic methods used for ECM analysis and also describe general labeling strategies for ECM visualization and imaging of the proteolytic reorganization of ECM as well as applications of Förster resonance energy transfer-based approaches to monitor ECM functions with a high spatiotemporal resolution. Baranger et al. (2014) discuss data on the endogenous MMP inhibitors in the CNS and regulation of MMP-mediated proteolysis in inflammatory, neurodegenerative and infectious diseases, and synthetic inhibitors of MMPs and the perspective of their therapeutic use. Berezin, Walmod, Filippov, and Dityatev (2014) provide a comprehensive overview of multiple strategies for targeting the ECM molecules and their metabolizing enzymes and receptors with antibodies, peptides, glycosaminoglycans, and other natural and synthetic compounds. They also discuss application of developing ECM-targeting drugs in Alzheimer's disease, epilepsy, schizophrenia, addiction, multiple sclerosis, Parkinson's disease, and cancer.

Neural ECM Scaffolds

The unique electrochemical connection at synapses is backed up by multiple mechanical connections linking the pre- and postsynaptic membranes to each other as well as to the surrounding ECM. Because of this intimate link between neurites and their synapses and the unique 3D architecture of the brain, it is so far impossible to artificially reconstruct the brain. Nevertheless, in the last part of this volume, we would like to address the questions how one could mimic a scaffold that can be used by neurons and glial cells to create neuronal connections that can be used to functionally replace damaged tissues (Estrada, Tekinay, & Müller, 2014). To do this, one does not only need to develop ways of creating surfaces or scaffolds, which would allow the growth of neurites and glia, but also ways to create electrochemical connections between the healthy brain tissue and implanted neuronal networks, as discussed by Simi, Amin, Maccione, Nieus, and Berdondini (2014). An alternative approach to create new functional brain tissue would be to implant neuronal stem cells in such a way that glial cells and neurons can rebuild the damaged scaffolds. In order to do this, we require however precise information how a stem cell compartment is maintained and...