Extreme Makeover: Synapse Edition

Understanding how synapses are formed during development and subsequently altered throughout life is essential for understanding the function and the remarkable malleability of the mature nervous system. While it is well known that synaptogenesis is a complex process that occurs over a protracted period of development, relatively little is known about the underlying mechanisms. Recent work has suggested that many structural components of synapses are preassembled, trafficked down axons to growth cones, and deposited at sites of contact with target cells, and that cell-cell signaling modulates the subsequent addition of pre- and postsynaptic components that are essential for synaptic function. These and other signals also modulate synaptic specificity, maturation, and maintenance. Identification of the repertoire of cell-cell signaling that mediates synaptogenesis, and understanding how each component works individually and in concert, is not only of intrinsic interest, but is also important for understanding both neurodevelopmental disorders such as autism and epilepsy and the plasticity in the mature brain that underlies learning, memory, and cognition.In this recently published book, Molecular Mechanisms of Synaptogenesis, nearly three dozen chapters divided into six parts provide a foundation for understanding synaptogenesis in the context of normal development, plasticity, and disease. In part 1, the insights obtained into mechanisms of synaptogenesis from different vertebrate and invertebrate model systems are summarized, from fly, worm, and mollusks to the classic vertebrate neuromuscular junction. Part 2 includes several chapters on the roles of cell adhesion and secreted molecules in synapse formation and maintenance, from cadherins and proto-cadherins, NCAM, SynCAM, neuroligins-neurexins, ephrins-Ephs, and extracellular matrix molecules such as thrombospondin to growth factors such as neurotrophins. In part 3, the transport of proteins to and from the synapse is summarized, while part 4 deals with the synaptic cytoskeleton and morphogenic signaling. Part 5 provides the requisite chapters on the interrelatedness of synaptogenesis in development and synaptic plasticity and learning and memory in mature brain. Part 6, perhaps the most speculative and thus the most interesting section of the volume, summarizes defects in synaptogenesis associated with neurodevelopmental disorders such as autism and disorders of the mature brain such as dementia.View Large Image | View Hi-Res Image | Download PowerPoint SlideAlthough new developments unfold so rapidly that any book cannot cover the field in its entirety, this volume provides a comprehensive overview and perspectives on the interplay between development, maturity, and disease that is valuable to the newcomer and expert alike. One strength of this volume is that it highlights the breadth of the many experimental systems and approaches that are used to study normal development as well as synaptic defects associated with human diseases. A second strength is that many chapters discuss the application of forward genetics, proteomic approaches, RNAi screens, etc. to identify novel molecular mechanisms that are important modulators of synapse formation and maintenance.There are several chapters that deserve special mention. One of these, by Heather Van Epps and Yi-Shi Jin, summarizes the work of their group and others on synaptogenesis using C. elegans and Drosophila as model systems. This chapter systematically leads the reader through both a description of worm and fly neuromuscular synapses and the forward genetics and other methodological approaches that have been used to great advantage to examine the formation of pre- and postsynaptic specializations, and it synthesizes a vast literature to clearly and concisely summarize the repertoire of cell-autonomous and nonautonomous mechanisms that underlie the formation of these synapses.A second chapter of note, by Rochelle Hines and Alaa El-Husseini, focuses on the mechanisms that regulate the clustering of proteins at pre- and postsynaptic sites. The authors discuss how posttranslational modifications of synaptic proteins, and their interactions with a large number of scaffolding proteins, modulate synapse formation and function. While Hines and El-Husseini focus on the protein-protein interactions that define postsynaptic specializations, a related chapter in a different section of the book does an equally admirable job reviewing the state of knowledge about the assembly of presynaptic active zones. The chapter by Thomas Dresbach, Anna Fejtova, and Eckart Gundelfinger provides an excellent summary of our current understanding of the steps in precursor vesicle assembly, including the role of members of the Piccolo-Bassoon family of proteins, the transport of Piccolo-Bassoon-containing transport vesicles from the cell body down the axon, and the subsequent accretion of proteins required for mature active zone function. These chapters provide a relatively complete view of the state of our understanding of the molecular interactions that underlie the formation of presynaptic terminals and postsynaptic neurotransmitter receptor clusters.Among the most stimulating parts of the book are the chapters included in the final section, entitled “Synaptogenesis and Brain Disorders.” Here the discussion centers on the synaptic abnormalities that are associated with neurodevelopmental disorders such as autism and Fragile X, and, compellingly, disorders of the mature brain such as schizophrenia, depression, Huntington's Disease, and dementia. As the editors note in their preface to the volume, this section “provides a new compilation of information that links changes in basic synapse structure to brain diseases.” This section highlights how researchers in this area can translate a basic understanding of mechanisms underlying synaptogenesis to eventual diagnoses and treatments of neurological disorders that have abnormal synapse formation, function, and/or connectivity as a hallmark. However, while synaptic dysfunction has been implicated in many of these disorders, the critical question of how defects in synaptogenesis cause cognitive defects has not been carefully studied, and this remains fertile ground for future work in this field.There are some limitations to the volume as well. As mentioned above, in fields such as this one that move forward very quickly, books are hard-pressed to include the most up-to-date information on every topic. There are a few examples of this in the volume, one of which is in the chapter focusing on neuroligin and neurexin and their roles in synaptogenesis. This chapter does not include discussion of a recent paper, coauthored by one of the chapter's authors, which suggested that neuroligins are dispensable for synapse formation (Varoqueaux et al., 2006xVaroqueaux, F., Aramuni, G., Rawson, R.L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Sudhof, T.C., and Brose, N. Neuron. 2006; 51: 741–754Abstract | Full Text | Full Text PDF | PubMed | Scopus (382)See all ReferencesVaroqueaux et al., 2006). This paper raised important issues about neuroligin-neurexin function, as it suggested that these molecules are important for synapse maturation and synaptic transmission, but not, as previously thought, for triggering initial synapse formation. A second limitation is that, for the most part, each chapter considers the molecules involved in the formation of pre- or postsynaptic specializations individually, but does not include discussion of how these pathways may converge or act in concert. Understanding the hierarchical nature of signaling mechanisms, and which are modulators rather than mediators, is a major challenge for researchers in this area. Finally, few chapters consider in detail the spatial and temporal relationships between synapse construction and the onset of synapse function. These limitations aside, this volume provides an excellent resource to both established investigators and newcomers to the field.