Sticky Synapse (eBook)

Dr. Michael Hortsch holds a Diploma degree in Biochemistry from the Free University Berlin and a Ph.D. in Biology from the University of Heidelberg in Germany. While working at the Weizmann Institute in Israel, the European Molecular Biology Laboratory in Heidelberg, and at the University of California at Berkeley he has published on topics such as the mechanism of growth factor receptor activation, the transport of proteins across membranes, and the physiological roles of neuronal cell adhesion molecules during nervous system development. He has been a faculty member of the Department of Cell and Developmental Biology at the University of Michigan in Ann Arbor since 1991. Dr. Hortsch has served on scientific review panels for the National Institutes of Health, the National Science Foundation, and other agencies.   Dr. Hisashi Umemori is a faculty member of the Molecular and Behavioral Neuroscience Institute and of the Department of Biological Chemistry at the University of Michigan Medical School. He worked with Dr. Tadashi Yamamoto at the Institute of Medical Sciences of the University of Tokyo and analyzed intracellular signaling mechanisms that are involved in myelination and in learning and memory. While working with Dr. Joshua R. Sanes at Washington University Medical School and at Harvard University, he identified synaptic organizing molecules that promote synapse formation during nervous system development. Dr. Umemori has received various awards, including a Basil O'Connor Award and a Klingenstein Fellowship Award.    

Preface 5
Contents 6
Contributors 8
A Short History of the Synapse - Golgi Versus Ramón y Cajal 12
References 19
Cell Adhesion Molecules at the Drosophila Neuromuscular Junction 21
2.1 Introduction 22
2.2 CAMs at the NMJ 25
2.2.1 Capricious 25
2.2.2 Connectin 25
2.2.3 Down Syndrome Cell Adhesion Molecule 26
2.2.4 Fasciclin II 26
2.2.5 Fasciclin III 27
2.2.6 Integrins 27
2.2.7 N-Cadherin 28
2.2.8 Neuroglian 28
2.2.9 Toll 29
2.3 CAMs and Neuromuscular Network Formation 29
2.3.1 Presynaptic Cell Pattern Formation 30
2.3.1.1 CAMs and Axon-ECM Adhesion 30
2.3.1.2 CAMs and Axon-Axon Adhesion 31
2.3.1.3 CAMs and Axon-Muscle Adhesion 31
2.3.2 Postsynaptic Cell Pattern Formation 32
2.4 CAM-Mediated Intracellular Signaling Activation at the NMJ 34
2.5 CAMs Mediate FORCES 36
2.6 CAMs in NMJ Plasticity 37
2.7 A Two-Step Model for CAM-Mediated NMJ Formation 37
2.7.1 Myopodia Brings CAMs Closer to Navigating Motor Axons 38
2.7.2 CAM-Mediated Postsynaptic Signaling Hub 39
2.8 CAMs: The Cellular Glue that Holds Our Thoughts Together 41
References 43
Development of the Vertebrate Neuromuscular Junction 48
3.1 Vertebrate Neuromuscular Junction: A Model Synapse 48
3.2 Vertebrate Neuromuscular Junction: The Basics 52
3.2.1 Motor Neurons and Their Presynaptic Terminals 53
3.2.2 The Postsynaptic Apparatus 56
3.2.3 Non-myelinating Perisynaptic Schwann Cells 57
3.2.4 The Synaptic Cleft and Basal Lamina 58
3.3 Morphological Development of the Vertebrate NMJ 61
3.3.1 Synaptic Differentiation 61
3.3.2 Synaptic Maturation and Maintenance 66
3.4 Trans-synaptic Cues Direct NMJ Formation and Maintenance 68
3.4.1 Historical Perspective 68
3.4.2 Synaptogenic Molecules Within Synaptic BL 69
3.4.3 Agrin 69
3.4.4 Laminins 70
3.4.5 Collagen IV 72
3.4.6 Nidogens 75
3.4.7 Other BL Components Contributing to NMJ Formation and Maintenance 75
3.4.8 Transmembrane Adhesion Molecules Contributing to NMJ Formation and Maintenance 79
3.5 Vertebrate Neuromuscular Junction: Concluding Remarks 81
References 81
Synapse Formation in the Mammalian Central Nervous System 94
4.1 Introduction 94
4.2 Structures and Molecules of CNS Synapses 95
4.2.1 Ultrastructure of CNS Synapses 95
4.2.2 Molecules at CNS Synapses 96
4.2.2.1 Presynaptic Scaffold Molecules in the CNS 97
Munc13-1 97
RIM1 97
Bassoon and Piccolo 98
CASK 98
4.2.2.2 Postsynaptic Scaffold Molecules in the CNS 99
Postsynaptic Scaffold Proteins at the Excitatory Synapse 99
The PSD95/SAP90 Family 99
ProSAP/Shank Family Proteins 99
Postsynaptic Scaffold Protein at the Inhibitory Synapse 100
Gephyrin 100
4.3 Synaptogenesis in the CNS 100
4.3.1 Initial Contact of the Axon with its Target and Differentiation of CNS Synapses 100
4.3.2 Maturation and Maintenance of CNS Synapses 102
4.4 Synaptogenic Molecules in the CNS 103
4.4.1 WNT7a 105
4.4.2 Neurexin/Neuroligin 106
4.4.3 SynCAM (or Nectin-Like Molecules) 106
4.4.4 FGF22 107
4.4.5 Narp 107
4.4.6 EphrinB 107
4.4.7 Thrombospondins 108
4.4.8 NGLs, SIRPs, and LRRTMs 108
4.5 Conclusions 108
References 109
Developmental Axonal Pruning and Synaptic Plasticity 116
5.1 Introduction 116
5.2 Stereotyped and Stochastic Axonal Pruning 117
5.3 Synapse Elimination in the Peripheral Nervous System 118
5.4 Axonal Pruning in the Central Nervous System 123
5.4.1 Axon Pruning in the Hippocampus: The Development of the Infrapyramidal Bundle 123
5.4.2 Axon Pruning in the Cerebellum: The Regression of Redundant Climbing Fibers 127
5.4.3 Axon Pruning in the Visual System 130
5.5 Synaptic Plasticity 135
5.6 Conclusions 140
References 140
Cell Adhesion Molecules in Synaptopathies 150
6.1 Introduction 150
6.2 Neuroligins and Neurexins 151
6.3 Contactin and Contactin-Associated Proteins 156
6.4 Cadherins and Protocadherins 159
6.5 CAMs Polymorphisms and the Susceptibility to Psychiatric Conditions 161
6.6 Conclusions and Perspectives 162
References 163
The Cadherin Superfamily in Synapse Formation and Function 168
7.1 Introduction 169
7.2 Classical Cadherins and Catenins 174
7.2.1 Roles in Axon Targeting 175
7.2.2 Roles in Dendrite and Dendritic Spine Morphogenesis 176
7.2.3 Roles in Synapse Formation and Maturation 177
7.2.4 Roles in Synapse Function and Plasticity 178
7.3 Protocadherins 180
7.3.1 Clustered Protocadherins 180
7.3.2 Fat-Type and 7-Transmembrane Protocadherins 183
7.3.3 delta-Protocadherins 185
7.4 Concluding Remarks 186
References 187
Nectins and Nectin-Like Molecules in the Nervous System 193
8.1 Introduction 193
8.2 General Properties of Nectins and Necls 195
8.3 Cell-Cell Adhesion Activity of Nectins and Necls 197
8.4 Nectins Form AJs Cooperatively with Cadherins 198
8.5 Interactions of Nectins with Other CAMs and a Growth Factor Receptor in Cell Adhesions 201
8.6 Involvement of Nectins and Cadherins in the Formation of Synapses 202
8.7 Involvement of Nectins in the Selective Association between Axons and Dendrites 207
8.8 Possible Roles of Nectins and Cadherins in Synapse Remodeling 207
8.9 Involvement of Necls in the Formation of Various Types of Cell-Cell Junctions in the Central and Peripheral Nervous Systems 208
8.10 Conclusions and Perspectives 209
References 210
The Down Syndrome Cell Adhesion Molecule 215
9.1 Introduction 215
9.2 Identification of DSCAM Family Members 216
9.3 General Domain Structure 217
9.4 DSCAM Molecular Diversity 218
9.5 Homophilic Interactions 221
9.6 Branch Segregation and Self-Avoidance 223
9.7 Tiling 225
9.8 Non-repulsive DSCAM Functions 226
9.9 Non-DSCAM Interactions 227
9.10 Concluding Remarks 228
References 228
Molecular Basis of Lamina-Specific Synaptic Connections in the Retina: Sidekick Immunoglobulin Superfamily Molecules 231
10.1 Introduction 231
10.2 The Role of Sdks in Laminar Specificity 232
10.2.1 Laminar Specificity Is a Major Determinant of Synaptic Specificity in the CNS 232
10.2.2 Laminar Organization of the Retina 233
10.2.3 Sdks Mediate Laminar Specificity 234
10.2.4 DSCAMs, Close Relatives of Sdks, Mediate Laminar Specificity 236
10.3 Molecular and Cellular Properties of Sdks 237
10.3.1 Structure and Expression of Sdks 237
10.3.2 Sdk Ectodomains Mediate Homophilic Adhesion 238
10.3.3 Intracellular Signaling of Sdks 239
10.4 Conclusions 240
References 240
SYG/Nephrin/IrreC Family of Adhesion Proteins Mediate Asymmetric Cell-Cell Adhesion in Development 243
11.1 The IrreC/Nephrin/SYG-1 Family of Proteins 243
11.2 SYG-1 and SYG-2 Encode Synaptic Target Choice of the HSNL Neuron in C. elegans 244
11.3 Kirre/DUF, IrreC/Roughest, SNS, and Hirbris Mediate Myoblast Fusion in Drosophila 248
11.4 Kirre/DUF, IrreC/Roughest, SNS, and Hirbris Are Required for Proper Patterning of the Drosophila Eye 249
11.5 Vertebrate NEPH1 and Nephrin Are Critical Proteins in Kidney Development 249
11.6 Summary 251
References 252
L1-Type Cell Adhesion Molecules: Distinct Roles in Synaptic Targeting, Organization, and Function 254
12.1 General Structure and Function of L1-Type Proteins 254
12.2 Synaptic Functions of L1-Type Cell Adhesion Molecules 257
12.2.1 L1-Type Cell Adhesion Molecules in Learning and Memory 257
12.2.2 L1-Type Cell Adhesion Molecules in Synapse Targeting 259
12.2.3 L1-Type Cell Adhesion Molecules in Synaptogenesis 260
12.2.4 L1-Type Cell Adhesion Molecules in Synaptic Transmission and Signaling 264
12.3 Conclusions and Outlook 264
References 265
Cell Adhesion Molecules of the NCAM Family and Their Roles at Synapses 271
13.1 Members of the NCAM Family of Cell Adhesion Molecules 272
13.2 Structure of NCAM Family Proteins 274
13.3 Posttranslational Modifications of NCAM Family Proteins 277
13.4 Extracellular Interaction Partners of NCAM Family Proteins 278
13.5 Intracellular Interaction Partners of NCAM Family Proteins 282
13.6 NCAM-Mediated Intracellular Signaling Pathways 284
13.7 Effects of Extracellular ATP on NCAM Function 284
13.8 Regulatory Roles for Polysialic Acid in NCAM1 Function 286
13.9 NCAM Protein in Long-Term Potentiation and Long-Term Depression 289
13.10 Conclusions 292
References 293
MHC Class I Function at the Neuronal Synapse 306
14.1 Background 306
14.2 MHC Class I Expression in Neurons 308
14.2.1 Surface Expression of Neuronal MHC Class I Molecules 310
14.3 Link to Synaptic Function 311
14.3.1 Synaptic Plasticity in the Developing and Adult Brain 311
14.3.2 Synaptic Elimination in the Axotomized Spinal Cord 312
14.4 Putative Neuronal MHC Class I Receptors 315
14.5 Non-synaptic Functions of Neuronal MHC Class I 317
14.5.1 Neuronal Susceptibility to Immune-Mediated Cytotoxicity 317
14.5.2 The Vomeronasal Organ 318
14.6 Association with Neurological Diseases 319
References 321
Pathfinding Molecules Branch Out: Semaphorin Family Members Regulate Synapse Development 325
15.1 Introduction 325
15.2 The Semaphorin Family 326
15.2.1 Discovery and Organization 326
15.2.2 Semaphorin Receptors 327
15.2.3 Biological Functions of Semaphorins and Their Receptors 328
15.3 Invertebrate Semaphorins Mediate Synapse Development 329
15.4 Vertebrate Semaphorins in Synapse Formation and Function 330
15.4.1 Class 3 Semaphorins 330
15.4.2 Class 4 Semaphorins 332
15.5 Conclusions 333
References 334
Ephrins and Eph Receptor Tyrosine Kinases in Synapse Formation 336
16.1 Introduction 336
16.2 The Eph Family: Description 337
16.3 Ephrins Control Neuromuscular Topography and Synapse Formation in the PNS 339
16.4 Ephs and Ephrins in Synapse Formation in the CNS 341
16.5 Summary and Future Directions 344
References 344
Neurexins and Neuroligins: A Synaptic Code for Neuronal Wiring That Is Implicated in Autism 349
17.1 Neurexins: Genes and Proteins Structure 349
17.2 Neurexin Genes Are Differentially Expressed 350
17.3 Dystroglycan and Neurexophilin - Neurexin-Interacting Proteins with Unknown Functions 353
17.4 Neuroligins: Genes and Proteins Structure 354
17.5 Splicing of Both Neurexins and Neuroligins Determines Affinity and Specificity of Their Interaction 355
17.6 The Role of Neurexins and Neuroligins in Synapse Formation and Stabilization 357
17.6.1 In Vitro Synapse Formation Assays 357
17.6.2 Intracellular Signaling of Neurexins and Neuroligins 358
17.6.3 The Link Between Cell Adhesion and Synaptic Plasticity 360
17.7 Neurexin and Neuroligin Gene Polymorphisms in Autism Spectrum Disorders and Mental Retardation 361
17.8 Conclusions, the Concept of a Synaptic Code and Future Directions 363
References 364
Synaptic Adhesion-Like Molecules (SALMs) 368
18.1 SALM Family Structure and Expression 369
18.2 SALM-Associated Proteins and Functional Significance 373
18.3 Homomeric and Heteromeric SALM Interactions 374
18.4 SALMs Promote Neurite Outgrowth 376
18.5 SALMs at the Synapse 378
18.6 Dual Functions for SALMs 379
References 381
The Role of Integrins at Synapses 385
19.1 Introduction 385
19.2 Integrins at CNS Synapses 387
19.2.1 Integrins and Synaptic Plasticity 387
19.2.2 Integrins and Memory 388
19.2.3 Integrins Modulate Neurotransmitter Receptors 389
19.2.4 Dendritic Spines and Integrins 390
19.3 Integrins in the Neuromuscular Junction Synapses 391
19.4 Role of Integrins in Synaptic Neuropathology 392
19.5 Concluding Remarks 392
References 393
Extracellular Matrix Molecules in Neuromuscular Junctions and Central Nervous System Synapses 396
20.1 Introduction 396
20.2 The Extracellular Matrix of the NMJ 397
20.2.1 Agrin 397
20.2.1.1 Alternative Splicing Controls Agrin Activity 399
20.2.1.2 Agrin Signal Transduction 400
20.2.1.3 Inducing Versus Stabilizing Postsynaptic Sites 400
20.2.1.4 The Antagonistic Role of Cholinergic Transmission 401
20.2.2 Laminins at the NMJ 402
20.2.3 Collagens 405
20.2.4 Matrix Components Involved in Synaptic Function 405
20.2.5 Proteases 406
20.2.6 Synapse-Specific Carbohydrates 407
20.2.7 Dystroglycan 408
20.2.8 Growth Factors 409
20.3 The Extracellular Matrix and CNS Synapses 410
20.3.1 Agrin in the CNS 411
20.3.2 Laminins in the CNS 411
20.3.3 Proteoglycans in the CNS Extracellular Matrix 412
20.3.4 Thrombospondins 413
20.4 Conclusions 414
References 415
Gap Junctions as Electrical Synapses 422
21.1 Introduction 422
21.2 Life History of a Gap Junction 423
21.3 The First Opening 426
21.4 Gap Junctions as Sites of Attachment 427
21.5 Specificity of Junction Formation in the Central Nervous System 429
21.6 Specificity of Gap Junction Formation Between Neurons 429
21.7 Why Electrical Coupling? 432
21.8 Gap Junctions in Development 433
21.9 A Fixation Artifact? 433
21.10 Pannexins/Innexins 433
References 434
Index 439