Dityatev / Wehrle-Haller / Pitk„nen Brain Extracellular Matrix in Health and Disease

1. Auflage 2014
ISBN: 978-0-444-63494-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band 214, 506 Seiten

Reihe: Progress in Brain Research

In the central nervous system, extracellular matrix (ECM) molecules, including hyaluronic acid, chondroitin and heparan sulfate proteoglycans, tenascins, reelin and agrin, along with their remodelling enzymes, such as neurotrypsin, neuropsin, plasminogen activators, and metalloproteinases, are secreted by neural and non-neural cells into the extracellular space to form the ECM and signal via ECM receptors. Despite recent advances in the ECM field, the importance of neural ECM for physiological and pathological processes is currently less widely recognized than that of other CNS elements. This book will enlighten recent progress in our understanding of mechanisms by which neural ECM, its receptors and activity-dependent ECM remodeling regulate neural development, synaptic plasticity, and contribute to pathological changes in the brain. In the first part, the roles of ECM signaling and proteolytic modification of ECM in neurogenesis, neural migration, axonal pathfinding, synaptogenesis, synaptic and homeostatic plasticity will be discussed. The second part will focus on the emerging ECM-dependent mechanisms associated with CNS injury, epilepsy, neurodegenerative and neuropsychiatric diseases. For further development of neural ECM field, a very important contribution is the third part of the book, which is devoted to neural ECM-targeting tools and therapeutics. The concluding fourth part will highlight advances in development of artificial ECM and ECM-based systems suitable for multisite recording and stimulation of neural cells. - Authors are the leading experts in the field of brain extracellular matrix in health and disease - Book covers the most important aspects of brain extracellular matrix in health and disease - Interesting for both scientists and clinicians

Autoren/Hrsg.

Dityatev, Alexander

Wehrle-Haller, Bernhard

Pitk„nen, Asla

Inhaltsverzeichnis

1;Front Cover;1
2;Brain Extracellular Matrix in Health and Disease;4
3;Copyright;5
4;Contributors;6
5;Preface;14
5.1;Functions of Neural ECM;14
5.2;Neural ECM in Brain Diseases;15
5.3;Neural ECM-Targeting Tools and Therapeutics;16
5.4;Neural ECM Scaffolds;16
5.5;References;17
6;Brain extracellular matrix meets COST-Matrix for European research networks;20
6.1;References;24
7;Contents;26
8;Part 1: Functions of Neural ECM;38
8.1;Chapter 1: Regulation of the neural stem cell compartment by extracellular matrix constituents;40
8.1.1;1. Neurogenesis Unfolds in Distinct Steps and Involves Neural Stem Cells;41
8.1.2;2. Molecular Determinants of Asymmetrical Division;41
8.1.3;3. Environmental Asymmetry and the Stem Cell Niche;42
8.1.4;4. The Stem Cell Niches of the Adult CNS;42
8.1.5;5. Tenascin Proteins in the NSC Niche;43
8.1.6;6. Expression of Tenascin Genes in Radial Glia and Astrocyte Progenitors;45
8.1.7;7. Expression of Tenascin Genes in Oligodendrocyte Progenitors;48
8.1.8;8. Regulation of Tenascin Genes in NSCs;50
8.1.9;9. Laminin Proteins in the Adult Stem Cell Niche;51
8.1.10;10. Chondroitin sulfate Proteoglycans in the NSC Compartment;52
8.1.11;11. Membrane-Based Part-Time CSPGs;53
8.1.12;12. HSPGs in the NSC Compartment;53
8.1.13;13. ECM Receptors in NSCs and Glial Progenitors;54
8.1.14;14. Conclusions;55
8.1.15;Acknowledgments;56
8.1.16;References;56
8.2;Chapter 2: Neural ECM and synaptogenesis;66
8.2.1;1. Introduction;66
8.2.2;2. Proteoglycans;67
8.2.2.1;2.1. Roles of Astrocyte-Derived ECM in Synaptogenesis In Vitro;67
8.2.2.2;2.2. Analysis of the ECM Functions by an In Vitro Model;68
8.2.2.3;2.3. Analysis of ECM Functions Using Genetically Modified Mice;69
8.2.3;3. Collagens and Synaptogenesis;70
8.2.3.1;3.1. Collagens in the ECM;70
8.2.3.2;3.2. Transmembrane Collagens;71
8.2.3.3;3.3. BM-Associated Collagens and ColQ;73
8.2.4;4. C1qDC Family Proteins;75
8.2.4.1;4.1. Profiles of C1qDC Family Members;75
8.2.4.2;4.2. C1q;76
8.2.4.3;4.3. Cbln1;77
8.2.5;5. Conclusion;78
8.2.6;Acknowledgments;79
8.2.7;References;79
8.3;Chapter 3: Neural ECM molecules in synaptic plasticity, learning, and memory;90
8.3.1;1. Introduction;91
8.3.2;2. Chondroitin Sulfate Proteoglycans;91
8.3.3;3. Hyaluronic Acid;97
8.3.4;4. Link Proteins;98
8.3.5;5. Tenascins;99
8.3.5.1;5.1. Tenascin-R;99
8.3.5.2;5.2. Tenascin-C;101
8.3.5.3;5.3. Tenascin-X;103
8.3.6;6. Heparan Sulfates Proteoglycans;103
8.3.7;7. Reelin;105
8.3.8;8. Conclusions and Perspectives;107
8.3.9;Acknowledgments;108
8.3.10;References;108
8.4;Chapter 4: Neural ECM molecules in axonal and synaptic homeostatic plasticity;118
8.4.1;1. Homeostatic Forms of Plasticity in the Nervous System;119
8.4.2;2. The ECM of the Brain;120
8.4.3;3. ECM Molecules Surrounding Synapses in the CNS;122
8.4.3.1;3.1. Perisynaptic ECM and Homeostatic Plasticity;122
8.4.4;4. Axon Initial Segment-specific ECM in Development and Plasticity;125
8.4.5;5. ECM Proteins in the Organization of Nodes of Ranvier;127
8.4.6;6. Questions and Directions of Future Research;130
8.4.7;Acknowledgments;131
8.4.8;References;131
8.5;Chapter 5: ECM receptors in neuronal structure, synaptic plasticity, and behavior;138
8.5.1;1. Introduction;138
8.5.2;2. Integrins;139
8.5.2.1;2.1. Introduction;139
8.5.2.2;2.2. Integrin Structure;139
8.5.2.3;2.3. Integrin ECM Ligands;140
8.5.2.4;2.4. Integrins in Synaptic Plasticity;142
8.5.2.4.1;2.4.1. Early Research;142
8.5.2.4.2;2.4.2. Integrin ß Subunits in Synaptic Plasticity;143
8.5.2.4.3;2.4.3. Integrin a Subunits in Synaptic Plasticity;144
8.5.2.5;2.5. Integrins in Learning and Memory;145
8.5.2.6;2.6. Signaling Downstream of Integrins;145
8.5.2.7;2.7. Integrins and Matrix Metalloproteases;146
8.5.2.8;2.8. Conclusion;147
8.5.3;3. Additional ECM Receptors;147
8.5.3.1;3.1. Membrane-Bound Heparan Sulfate Proteoglycans;147
8.5.3.1.1;3.1.1. Syndecans;147
8.5.3.1.2;3.1.2. Agrin;149
8.5.3.2;3.2. Lipoprotein Receptors;150
8.5.3.2.1;3.2.1. ApoER2;151
8.5.3.2.2;3.2.2. VLDLR;151
8.5.3.2.3;3.2.3. Low-Density LRP;152
8.5.3.3;3.3. Tetraspanins;153
8.5.3.4;3.4. L-Type Voltage-Dependent Calcium Channels;153
8.5.4;4. Link to Human Brain Disease;154
8.5.4.1;4.1. Integrin Links to Human Brain Disease;154
8.5.4.2;4.2. LDLRs and Alzheimer's Disease;155
8.5.5;5. Questions and Directions for Future Research;156
8.5.6;Acknowledgments;156
8.5.7;References;157
9;Part 2: Neural ECM in Brain Diseases;170
9.1;Chapter 6: Neural ECM proteases in learning and synaptic plasticity;172
9.1.1;1. Expression and Activation of the ECM Proteases in Neurons;173
9.1.1.1;1.1. Serine Proteases;173
9.1.1.1.1;1.1.1. Tissue Plasminogen Activator;173
9.1.1.1.2;1.1.2. Neuropsin;173
9.1.1.1.3;1.1.3. Neurotrypsin;173
9.1.1.2;1.2. Matrix Metalloproteinases;174
9.1.2;2. ECM-Degrading Enzymes in the Modulation of PNNS and Synaptic Remodeling During Plasticity, with Emphasis on the Enriched E;176
9.1.3;3. MMP-9 in Long-term Potentiation and Learning;178
9.1.4;4. The Tissue plasminogen Activator/plasmin System;180
9.1.5;5. Neuropsin in Synaptic Plasticity and Behavior;181
9.1.6;6. Neurotrypsin in Synaptic Plasticity, Learning, and Memory;183
9.1.7;7. Clinical Relevance of Extracellular Proteolysis in Psychiatric Conditions;184
9.1.8;Acknowledgments;185
9.1.9;References;186
9.2;Chapter 7: Neural ECM in laminar organization and connectivity development in healthy and diseased human brain;196
9.2.1;1. Introduction;197
9.2.2;2. The ECM of the Early Human Fetal Telencephalon;197
9.2.3;3. Neural ECM in Laminar Organization and Connectivity Development of the Human Telencephalon During the Midfetal Period;199
9.2.4;4. Neuronal ECM in Laminar Organization and Connectivity Development in the Third Gestational Trimester and Early Postnatal P;201
9.2.5;5. Neural ECM in Diseased Developing Human Brain;202
9.2.5.1;5.1. Neural ECM in Malformations of Cortical Development;202
9.2.5.2;5.2. Neural ECM and Other Complex Neurodevelopmental Disorders;206
9.2.6;6. Relevance of Vulnerability, Plasticity, and Diagnostics and Perspective for Therapeutic Approaches in Developmental Brain ;207
9.2.7;Acknowledgments;208
9.2.8;References;208
9.3;Chapter 8: Neural ECM in regeneration and rehabilitation;216
9.3.1;1. Introduction;216
9.3.2;2. The Compositions of ECM in the CNS;217
9.3.2.1;2.1. Structure of CSPGs;217
9.3.2.2;2.2. CSPGs in the Perineuronal Nets;217
9.3.3;3. Pathophysiology of ECM in CNS Disorders;218
9.3.3.1;3.1. Neurodegenerative Diseases;218
9.3.3.2;3.2. Brain Tumor;219
9.3.3.3;3.3. CNS Injury;220
9.3.4;4. ECM in Plasticity and Rehabilitation;220
9.3.4.1;4.1. Fear Memory;220
9.3.4.2;4.2. Novel Object Recognition Memory;221
9.3.4.3;4.3. Visual Cortex;221
9.3.4.4;4.4. Somatosensory Cortex/Barrel Cortex;222
9.3.4.5;4.5. Promoting Functional Recovery in CNS Injury: Stroke;222
9.3.4.6;4.6. Promoting Functional Recovery in CNS Injury: Spinal Cord Injury;223
9.3.5;5. Conclusion;223
9.3.6;Acknowledgments;224
9.3.7;References;224
9.4;Chapter 9: On the Structure and functions of gelatinase B/Matrix metalloproteinase-9 in neuroinflammation;230
9.4.1;1. Introduction;230
9.4.2;2. MMP-9 Is an Inflammatory Proteinase;231
9.4.3;3. The REGA Model of Autoimmunity in MS;234
9.4.4;4. Evidences for Different MMP-9 Forms in Neuroinflammation;236
9.4.5;5. Technological Aspects of MMP-9 Tests;238
9.4.6;6. Concluding Remarks and Future Challenges;239
9.4.7;Acknowledgments;239
9.4.8;References;239
9.5;Chapter 10: ECM in brain aging and dementia;244
9.5.1;1. Introduction;245
9.5.2;2. Role of Heparan Sulfate Proteoglycans in Dementia;245
9.5.3;3. The Role of the ECM in Age-Related Neurodegeneration and Extracellular Space Diffusivity;248
9.5.4;4. CSPG-based Perineuronal Nets and Axonal Coats as a Specialized Form of the ECM;250
9.5.4.1;4.1. PNs and ACs in AD;251
9.5.5;5. MMPs in Brain Aging and Dementia;253
9.5.5.1;5.1. MMPs in AD;253
9.5.5.2;5.2. Other MMPs Involved in the Processing of APP and the Pathogenesis of AD;254
9.5.6;6. Conclusions;255
9.5.7;Acknowledgments;255
9.5.8;References;256
9.6;Chapter 11: Neural ECM and epilepsy;266
9.6.1;1. Introduction;267
9.6.2;2. Urokinase-Type Plasminogen Activator Receptor Interactome in Epileptogenesis and Epilepsy;267
9.6.2.1;2.1. Urokinase-Type Plasminogen Activator Receptor;268
9.6.2.2;2.2. Extracellular Ligands of uPAR;270
9.6.2.2.1;2.2.1. Urokinase-Type Plasminogen Activator;270
9.6.2.2.2;2.2.2. Vitronectin;270
9.6.2.2.3;2.2.3. Sushi-Repeat Protein X-Linked 2;270
9.6.2.2.4;2.2.4. Kininogen;271
9.6.2.3;2.3. Lateral Partners of uPAR;271
9.6.2.3.1;2.3.1. Formyl Peptide G Protein-Coupled Receptor (FPRL1);271
9.6.2.3.2;2.3.2. LDL Receptor-Related Protein 1;271
9.6.2.3.3;2.3.3. Platelet-Derived Growth Factor Receptor-ß;271
9.6.2.3.4;2.3.4. Integrins;272
9.6.2.4;2.4. Conclusion;272
9.6.3;3. Matrix Metalloproteinases in Epileptogenesis and Epilepsy;272
9.6.4;4. ECM Components of Perineuronal Nets and Epileptogenesis;275
9.6.5;5. LGI1 and Epilepsy;276
9.6.5.1;5.1. LGI1 Protein;276
9.6.5.2;5.2. Association Between LGI1 and TLE;277
9.6.5.2.1;5.2.1. LGI1 Mutations Associated with Epilepsy;277
9.6.5.2.2;5.2.2. Interaction with Kv1.1;278
9.6.5.2.3;5.2.3. Interaction with ADAM22 and ADAM23;278
9.6.5.2.4;5.2.4. Developmental Role of LGI1;280
9.6.5.3;5.3. Conclusion;281
9.6.6;6. Imaging ECM During Epileptogenesis and Epilepsy;281
9.6.6.1;6.1. Neuroimaging During Epileptogenesis and Epilepsy;281
9.6.6.2;6.2. ECM Brain Imaging;282
9.6.7;7. ECM and Neuropsychiatric Comorbidities: Links to Autism and Schizophrenia;283
9.6.7.1;7.1. Matrix Metalloproteinase-9;283
9.6.7.2;7.2. Reelin;284
9.6.7.3;7.3. Urokinase Plasminogen Activator Receptor;284
9.6.7.4;7.4. Heparan Sulfate Proteoglycans;285
9.6.7.5;7.5. Chondroitin Sulfate Proteoglycans;286
9.6.8;8. Conclusions;286
9.6.9;Acknowledgments;286
9.6.10;References;287
9.7;Chapter 12: Neural ECM in addiction, schizophrenia, and mood disorder;300
9.7.1;1. Introduction;301
9.7.1.1;1.1. The Extracellular Matrix in the Central Nervous System;301
9.7.1.2;1.2. Implication of Neural ECM in Psychiatric Disorders;301
9.7.2;2. Drug Addiction;302
9.7.2.1;2.1. Opioids;302
9.7.2.2;2.2. Psychostimulants;305
9.7.2.3;2.3. Alcohol;307
9.7.2.4;2.4. Commonalities of Addictive Drugs on ECM;308
9.7.3;3. Schizophrenia;309
9.7.3.1;3.1. PNNs and Schizophrenia;309
9.7.3.2;3.2. Reelin and Schizophrenia;311
9.7.4;4. Mood Disorders;312
9.7.4.1;4.1. PNNs and Mood Disorders;312
9.7.4.2;4.2. Reelin and Mood Disorders;312
9.7.5;5. Conclusions and Future Directions;313
9.7.6;Acknowledgements;315
9.7.7;References;315
10;Part 3: Neural ECM-Targeting Tools and Therapeutics;322
10.1;Chapter 13: Current microscopic methods for the neural ECM analysis;324
10.1.1;1. Introduction;325
10.1.2;2. Microscopic Methods;326
10.1.2.1;2.1. Atomic Force Microscopy;326
10.1.2.2;2.2. Scanning Electron Microscopy;326
10.1.2.3;2.3. Autofluorescence Lifetime Microscopy;327
10.1.2.4;2.4. Confocal Reflection Microscopy;327
10.1.2.5;2.5. Multiphoton-Excitation Microscopy and Second-Harmonic Imaging Microscopy;328
10.1.2.6;2.6. Optical Coherence Tomography;329
10.1.2.7;2.7. Fourier Transform Infrared Microspectroscopy;329
10.1.2.8;2.8. Superresolution Imaging of Neural ECM;330
10.1.3;3. Labeling Strategies to Analyze Structure and Proteolytic Remodeling of ECM;330
10.1.3.1;3.1. Labeling of Glycans in the Neural Extracellular Matrix;330
10.1.3.2;3.2. Immunodetection of Proteolytically Unmasked Epitopes;333
10.1.3.3;3.3. Fluorochrome Labels to Monitor ECM Proteolysis;334
10.1.3.4;3.4. Application of DQ Substrates;334
10.1.3.5;3.5. Zymographic Assays;335
10.1.4;4. FRET-based Methods for the Investigation of ECM;336
10.1.4.1;4.1. Fluorescence Lifetime Approaches;337
10.1.4.2;4.2. Intensity-Based FRET Approaches;337
10.1.4.3;4.3. Application of FRET for Analysis of ECM;338
10.1.4.4;4.4. Application of FRET-Based Biosensors to Study ECM and ECM-Mediated Signaling;340
10.1.5;5. Conclusion;342
10.1.6;Acknowledgments;343
10.1.7;References;343
10.2;Chapter 14: Endogenous and synthetic MMP inhibitors in CNS physiopathology;350
10.2.1;1. A Brief History of the MMP/TIMP System, from the Nonspecific Degradation of ECM Proteins to Involvement in Animal Behavior;351
10.2.1.1;1.1. Structural and Functional Features of MMPs;352
10.2.1.2;1.2. Regulation of MMP Expression and Activity;354
10.2.2;2. TIMPs and Other Endogenous MMP Inhibitors;354
10.2.2.1;2.1. TIMPs in CNS Development and Pathophysiology;355
10.2.3;3. Regulation of MMPs and TIMPs in CNS Diseases;357
10.2.3.1;3.1. The MMP/TIMP System in Experimental Autoimmune Encephalomyelitis (EAE) and Multiple Sclerosis (MS);357
10.2.3.1.1;3.1.1. MMPs in EAE and MS;357
10.2.3.1.2;3.1.2. TIMPs, MMPIs, and Modulators of MMPs in EAE and MS;359
10.2.3.1.3;3.1.3. Conclusion;360
10.2.3.2;3.2. The MMP/TIMP System in Alzheimer's Disease;360
10.2.3.2.1;3.2.1. MMPs in Alzheimer's Disease;360
10.2.3.2.2;3.2.2. TIMPs and MMPIs in Alzheimer's disease;361
10.2.3.2.3;3.2.3. Conclusion;362
10.2.3.3;3.3. The MMP/TIMP System and TACE in Meningitis and Infection;363
10.2.3.3.1;3.3.1. Clinical and Epidemiological Aspects of Bacterial Meningitis;363
10.2.3.3.2;3.3.2. Pathophysiology of Brain Damage During Bacterial Meningitis;363
10.2.3.3.3;3.3.3. The Role of MMPs in the Pathogenesis of Bacterial Meningitis;364
10.2.3.3.4;3.3.4. TACE Inhibition;366
10.2.3.3.5;3.3.5. Imbalance of MMP/TIMP Activity;366
10.2.3.3.6;3.3.6. Aseptic Meningitis;366
10.2.3.4;3.4. MMP/TACE Inhibitors in Bacterial Meningitis;367
10.2.3.4.1;3.4.1. Cortical Injury;367
10.2.3.4.2;3.4.2. Hippocampal Apoptosis;367
10.2.3.4.3;3.4.3. Neurofunctional Outcome;369
10.2.3.4.4;3.4.4. Timing of Interventions;369
10.2.3.4.5;3.4.5. TACE Inhibition may be a Double-Edged Sword;369
10.2.3.4.6;3.4.6. Conclusion;369
10.2.4;4. Chemistry-based MMP Inhibitors, Perspectives for Their Use in the Treatment of CNS Diseases;370
10.2.4.1;4.1. Current Families of Chemistry-Based MMPIs;370
10.2.4.2;4.2. Blood-Brain Barrier Permeable MMPIs;373
10.2.4.3;4.3. Perspectives for the Use of MMPIs in the Treatment of CNS Diseases;374
10.2.5;Acknowledgments;375
10.2.6;References;375
10.3;Chapter 15: Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases;390
10.3.1;1. Introduction;391
10.3.2;2. ECM Targeting in CNS Diseases;391
10.3.2.1;2.1. Regeneration and After Stroke Rehabilitation;392
10.3.2.2;2.2. Aging and Alzheimer's Disease;393
10.3.2.3;2.3. Epilepsy, Schizophrenia, and Addiction;394
10.3.3;3. Targeting ECM Metabolizing Enzymes in CNS Diseases;395
10.3.3.1;3.1. ECM-Degrading Proteases;395
10.3.3.2;3.2. Endogenous Modulators of ECM-Degrading Proteases;396
10.3.3.3;3.3. Methods for Targeting ECM-Modulating Enzymes;396
10.3.3.3.1;3.3.1. Targeting at the Transcriptional and Translational Levels;397
10.3.3.3.2;3.3.2. Targeting Enzyme Activity;398
10.3.3.4;3.4. Drugs Targeting ECM-Modulating Enzymes;399
10.3.3.4.1;3.4.1. Multiple Sclerosis;399
10.3.3.4.2;3.4.2. Alzheimer's Disease;403
10.3.3.4.3;3.4.3. Hypoxia and Ischemia;403
10.3.3.4.4;3.4.4. Cancer;404
10.3.4;4. Integrin Targeting in CNS Diseases;405
10.3.4.1;4.1. Glioblastoma;405
10.3.4.2;4.2. Multiple sclerosis and Neuroinflammation;406
10.3.4.3;4.3. Injury and Stroke;406
10.3.4.4;4.4. Epilepsy;407
10.3.4.5;4.5. Alzheimer's Disease;408
10.3.5;5. Targeting CAMs in CNS Diseases;408
10.3.5.1;5.1. Thy-1 Membrane Glycoprotein, Thy-1;409
10.3.5.2;5.2. Coxsackievirus and Adenovirus Receptor, CAR;409
10.3.5.3;5.3. Intercellular Adhesion Molecule 5;412
10.3.5.4;5.4. Neural Cell Adhesion Molecule 1;412
10.3.5.5;5.5. Neural Cell Adhesion Molecule L1;412
10.3.5.6;5.6. Leucine-Rich Repeat Containing 15;413
10.3.6;6. Conclusions;413
10.3.7;Acknowledgements;413
10.3.8;References;413
11;Part 4: Neural ECM Scaffolds;426
11.1;Chapter 16: Neural ECM mimetics;428
11.1.1;1. ECM Mimetics on the Rise;428
11.1.2;2. The Extracellular Matrix;429
11.1.3;3. Interaction of ECM Scaffold and Host ECM;432
11.1.4;4. ECM Mimetics;433
11.1.5;5. Biomedical Neural ECM Mimetics;436
11.1.5.1;5.1. Naturally Derived ECM Mimetics;436
11.1.5.1.1;5.1.1. Collagen;436
11.1.5.1.2;5.1.2. HA-Derived Materials;436
11.1.5.1.3;5.1.3. Alginate;437
11.1.5.1.4;5.1.4. Agarose;437
11.1.5.1.5;5.1.5. Matrigel;437
11.1.5.1.6;5.1.6. Chitosan;438
11.1.5.1.7;5.1.7. Fibrin;438
11.1.5.1.8;5.1.8. Fibronectin;438
11.1.5.2;5.2. Synthetic ECM Mimetics;439
11.1.5.2.1;5.2.1. Polyethylene Glycol;439
11.1.5.2.2;5.2.2. Lactide- and Glycolide-Derived Polyesters;440
11.1.5.2.3;5.2.3. Polycaprolactones;440
11.1.5.2.4;5.2.4. Poly(2-hydroxyethyl Methacrylate);441
11.1.5.2.5;5.2.5. NeuroGel;441
11.1.5.2.6;5.2.6. Nanostructured Materials;441
11.1.5.2.7;5.2.7. Self-assembling Materials;441
11.1.6;6. Lost in Translation;442
11.1.7;Acknowledgments;443
11.1.8;References;443
11.2;Chapter 17: Integration of microstructured scaffolds, neurons, and multielectrode arrays;452
11.2.1;1. Introduction;452
11.2.2;2. Neurons and Neuroelectronic Micro-/nanostructured Substrates;454
11.2.3;3. Primary Neuronal Cultures on Neuroelectronic Substrates;456
11.2.3.1;3.1. Preparing and Growing Neural Cultures on Passive and Active Chips;456
11.2.4;4. Growing Neuronal Networks with Imposed Topologies;459
11.2.4.1;4.1. Compartmentalizing Neural Growth by Physical Confinement;460
11.2.4.2;4.2. Patterning Neural Networks by Surface Functionalization and Nanomaterials;460
11.2.5;5. 3D Neuronal Cultures and Challenges for Neuroelectronic Interfacing;465
11.2.6;6. Emerging Network Properties Induced by Different Surface Functionalizations and Network Topologies;468
11.2.6.1;6.1. Influences of the Substrate Functionalization on the Emergent Network Activity;468
11.2.6.2;6.2. Influences of the Network Topology on the Emergent Network Activity;469
11.2.7;7. Conclusions;473
11.2.8;Acknowledgments;473
11.2.9;References;474
11.3;Chapter 18: Intracellular signaling and perception of neuronal scaffold through integrins and their adapter proteins;480
11.3.1;1. Introduction;480
11.3.2;2. Integrin Structure Function Relationship;482
11.3.3;3. Mechanosignaling in Integrin-Dependent Cell-Matrix Adhesions;485
11.3.4;4. Mechanism of Paxillin Recruitment to Cell-Matrix Adhesions;486
11.3.5;5. Paxillin, at the Origin of an Integrin-Mediated Signaling Hub;488
11.3.6;6. Integrin Signaling and LTP at the Synapse;489
11.3.7;7. Conclusion;490
11.3.8;Acknowledgments;490
11.3.9;References;490
12;Index;498
13;Other Volumes in Progress in Brain Research;508

Leseproben

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. Miloševic, Judaš, 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...