CYY-1/cyclin Y and CDK-5 differentially regulate synapse elimination and formation for rewiring neural circuits

The assembly and maturation of neural circuits require a delicate balance between synapse formation and elimination. The cellular and molecular mechanisms that coordinate synaptogenesis and synapse elimination are poorly understood. In C. elegans, DD motoneurons respecify their synaptic connectivity during development by completely eliminating existing synapses and forming new synapses without changing cell morphology. Using loss- and gain-of-function genetic approaches, we demonstrate that CYY-1, a cyclin box-containing protein, drives synapse removal in this process. In addition, cyclin-dependent kinase-5 (CDK-5) facilitates new synapse formation by regulating the transport of synaptic vesicles to the sites of synaptogenesis. Furthermore, we show that coordinated activation of UNC-104/Kinesin3 and Dynein is required for patterning newly formed synapses. During the remodeling process, presynaptic components from eliminated synapses are recycled to new synapses, suggesting that signaling mechanisms and molecular motors link the deconstruction of existing synapses and the assembly of new synapses during structural synaptic plasticity.     

Mechanisms of synapse assembly and disassembly

The mechanisms that govern synapse formation and elimination are fundamental to our understanding of neural development and plasticity. The wiring of neural circuitry requires that vast numbers of synapses be formed in a relatively short time. The subsequent refinement of neural circuitry involves the formation of additional synapses coincident with the disassembly of previously functional synapses. There is increasing evidence that activity-dependent plasticity also involves the formation and disassembly of synapses. While we are gaining insight into the mechanisms of both synapse assembly and disassembly, we understand very little about how these phenomena are related to each other and how they might be coordinately controlled to achieve the precise patterns of synaptic connectivity in the nervous system. Here, we review our current understanding of both synapse assembly and disassembly in an effort to unravel the relationship between these fundamental developmental processes.     

Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes

Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of presynaptic and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses.     

Cell adhesion molecules regulating astrocyte–neuron interactions

A tripartite synapse comprises a neuronal presynaptic axon and a postsynaptic dendrite, which are closely ensheathed by a perisynaptic astrocyte process. Through their structural and functional association with thousands of neuronal synapses, astrocytes regulate synapse formation and function. Recent work revealed a diverse range of cell adhesion–based mechanisms that mediate astrocyte–synapse interactions at tripartite synapses. Here, we will review some of these findings unveiling a highly dynamic bidirectional signaling between astrocytes and synapses, which orchestrates astrocyte morphological maturation and synapse development. Moreover, we will discuss the roles of these newly discovered molecular pathways in brain physiology and function both in health and disease.     

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.     

Cell adhesion molecules: signalling functions at the synapse

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.     

Possible mechanisms of synapse formation during ontogenesis

Electron microscopic investigation of synaptogenesis in the sensomotor cortex and in the caudate nucleus has been performed in the prenatal ontogenesis (16-22 days) and in newborn rats. The first immature synapses are demonstrated to appear beginning on the 16th day of embryogenesis. At the end of the prenatal development and especially in newborn animals desmosome-like, asymmetric and symmetric, mixed and complex forms of the synaptic contacts are revealed. As a result of the analysis performed on the ultrastructural organization of the contacts, a hypothesis explaining mechanisms of development of various elements of the synapses has been suggested. A part of the synaptic contacts of the asymmetric and symmetric types is supposed to be genetically programmed and membrane specialization of these contacts is formed earlier than synaptic vesicles appear. Other part of the synapses undergoes certain stages of differentiation before the functionally mature contact is formed. The initial stage in the synapses formation in formation of the desmosome-like junction. The second stage is appearance of synaptic vesicles in the area of this contact. The third stage includes development of pre- and postsynaptic membranous specialization and owing to this the contact acquires either asymmetric or symmetric appearance. For the ontogenetic periods investigated establishment of complex forms of the intercellular junctions (tangent, reciprocal, etc.) is specific; this evidently demonstrates certain plastic rearrangements in the synapses during the process of development.     

Activity-dependent regulation of synaptic size in Drosophila neuromuscular junctions

One of the fundamental questions in neural development is how neurons form synapses of the appropriate size for the efficient transfer of information across neural circuits. Here we investigated the mechanisms that bring about the size correlation between synapses and postsynaptic cells during development of Drosophila neuromuscular junctions (NMJs). To do this, we made use of a unique system in which two neighboring muscles (M6 and M7) are innervated by the same neurons. In mature NMJs, synaptic size on M6 is normally larger than that on M7, in accordance with the difference in muscle volume; this ensures the same extent of contraction of both muscles, and we refer to this correspondence as "matching". We found that matching was apparent in larvae 8 h after hatching, but not in newly hatched larvae despite the difference in muscle volume. When sensory inputs were suppressed by the expression of tetanus toxin in sensory neurons, matching did not occur, although synapses were able to grow. Matching was also suppressed by the inhibition of motoneuronal activity. These results suggest that matching is induced by regulating the rate of synaptic growth on M6 and M7 in an experience- and activity-dependent manner. It seems most likely that retrograde signals from the postsynaptic to the presynaptic cell convey the information about muscle cell size. We thus examined whether a candidate of retrograde signaling in NMJs, BMP signaling, is involved in matching. However, there was no effect on matching in BMP type II receptor gene mutants, suggesting that other experience-driven mechanisms besides BMP signaling are involved in the proper development of synapses.     

Depression-biased reverse plasticity rule is required for stable learning at top-down connections

Top-down synapses are ubiquitous throughout neocortex and play a central role in cognition, yet little is known about their development and specificity. During sensory experience, lower neocortical areas are activated before higher ones, causing top-down synapses to experience a preponderance of post-synaptic activity preceding pre-synaptic activity. This timing pattern is the opposite of that experienced by bottom-up synapses, which suggests that different versions of spike-timing dependent synaptic plasticity (STDP) rules may be required at top-down synapses. We consider a two-layer neural network model and investigate which STDP rules can lead to a distribution of top-down synaptic weights that is stable, diverse and avoids strong loops. We introduce a temporally reversed rule (rSTDP) where top-down synapses are potentiated if post-synaptic activity precedes pre-synaptic activity. Combining analytical work and integrate-and-fire simulations, we show that only depression-biased rSTDP (and not classical STDP) produces stable and diverse top-down weights. The conclusions did not change upon addition of homeostatic mechanisms, multiplicative STDP rules or weak external input to the top neurons. Our prediction for rSTDP at top-down synapses, which are distally located, is supported by recent neurophysiological evidence showing the existence of temporally reversed STDP in synapses that are distal to the post-synaptic cell body.     

Characteristics and plasticity of electrical synaptic transmission

Electrical synapses are an omnipresent feature of nervous systems, from the simple nerve nets of cnidarians to complex brains of mammals. Formed by gap junction channels between neurons, electrical synapses allow direct transmission of voltage signals between coupled cells. The relative simplicity of this arrangement belies the sophistication of these synapses. Coupling via electrical synapses can be regulated by a variety of mechanisms on times scales ranging from milliseconds to days, and active properties of the coupled neurons can impart emergent properties such as signal amplification, phase shifts and frequency-selective transmission. This article reviews the biophysical characteristics of electrical synapses and some of the core mechanisms that control their plasticity in the vertebrate central nervous system.     

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.     

Cadherin-9 regulates synapse-specific differentiation in the developing hippocampus

Our understanding of mechanisms that regulate the differentiation of specific classes of synapses is limited. Here, we investigate the formation of synapses between hippocampal dentate gyrus (DG) neurons and their target CA3 neurons and find that DG neurons preferentially form synapses with CA3 rather than DG or CA1 neurons in culture, suggesting that specific interactions between DG and CA3 neurons drive synapse formation. Cadherin-9 is expressed selectively in DG and CA3 neurons, and downregulation of cadherin-9 in CA3 neurons leads to a selective decrease in the number and size of DG synapses onto CA3 neurons. In addition, loss of cadherin-9 from DG or CA3 neurons in vivo leads to striking defects in the formation and differentiation of the DG-CA3 mossy fiber synapse. These observations indicate that cadherin-9 bidirectionally regulates DG-CA3 synapse development and highlight the critical role of differentially expressed molecular cues in establishing specific connections in the mammalian brain.     

AMPA receptor trafficking: a road map for synaptic plasticity

Most excitatory transmission in the brain is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA receptors). Therefore, the presence of these receptors at synapses has to be carefully regulated in order to ensure correct neuronal communication. Interestingly, AMPA receptors are not static components of synapses. On the contrary, they are continuously being delivered and removed in and out of synapses in response to neuronal activity. This dynamic behavior of AMPA receptors is an important mechanism to modify synaptic strength during brain development and also during experience-dependent plasticity. AMPA receptor trafficking involves an intricate network of protein-protein interactions that start with the biosynthesis of the receptors, continues with their transport along dendrites, and ends with their local insertion and removal from synapses. The molecular and cellular mechanisms that regulate each of these processes, and their importance for synaptic plasticity, are now starting to be unraveled.     

Selective regulation of neurite extension and synapse formation by the beta but not the alpha isoform of CaMKII

Neurite extension and branching are important neuronal plasticity mechanisms that can lead to the addition of synaptic contacts in developing neurons and changes in the number of synapses in mature neurons. Here we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates movement, extension, and branching of filopodia and fine dendrites as well as the number of synapses in hippocampal neurons. Only CaMKIIbeta, which peaks in expression early in development, but not CaMKIIalpha, has this morphogenic activity. A small insert in CaMKIIbeta, which is absent in CaMKIIalpha, confers regulated F-actin localization to the enzyme and enables selective upregulation of dendritic motility. These results show that the two main neuronal CaMKII isoforms have markedly different roles in neuronal plasticity, with CaMKIIalpha regulating synaptic strength and CaMKIIbeta controlling the dendritic morphology and number of synapses.     

EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation

The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.     

Activity‐dependent regulation of synaptic size in Drosophila neuromuscular junctions

One of the fundamental questions in neural development is how neurons form synapses of the appropriate size for the efficient transfer of information across neural circuits. Here we investigated the mechanisms that bring about the size correlation between synapses and postsynaptic cells during development of Drosophila neuromuscular junctions (NMJs). To do this, we made use of a unique system in which two neighboring muscles (M6 and M7) are innervated by the same neurons. In mature NMJs, synaptic size on M6 is normally larger than that on M7, in accordance with the difference in muscle volume; this ensures the same extent of contraction of both muscles, and we refer to this correspondence as “matching”. We found that matching was apparent in larvae 8 h after hatching, but not in newly hatched larvae despite the difference in muscle volume. When sensory inputs were suppressed by the expression of tetanus toxin in sensory neurons, matching did not occur, although synapses were able to grow. Matching was also suppressed by the inhibition of motoneuronal activity. These results suggest that matching is induced by regulating the rate of synaptic growth on M6 and M7 in an experience‐ and activity‐dependent manner. It seems most likely that retrograde signals from the postsynaptic to the presynaptic cell convey the information about muscle cell size. We thus examined whether a candidate of retrograde signaling in NMJs, BMP signaling, is involved inmatching. However, there was no effect on matching inBMP type II receptor gene mutants, suggesting thatother experience‐driven mechanisms besides BMP signaling are involved in the proper development of synapses. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006     

Neurotrophin regulation of synaptic transmission

Examples of signaling molecules that are devoted to neuronal development at the exclusion of other functions are scarce. It may then come as no surprise to learn that a family of molecules that promote neuronal survival, differentiation and outgrowth also regulate synaptic transmission at both developing and mature synapses. Indeed, many studies over the past five years have shown that neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), NT-4/5 and brain-derived neurotrophic factor (BDNF), have both rapid and long-latency influences on synaptic strength. New research has highlighted the enormous range of neurotrophin actions at both developing and mature synapses, demonstrating that transmission can be enhanced or reduced at excitatory and inhibitory synapses by either pre- or postsynaptic mechanisms.     

Presynaptic function

Changing the strength of synapses is key to the adaptive modifications of what neuronal circuits compute. Unsurprisingly, many different mechanisms have evolved to alter synaptic strength. Some of these mechanisms depend on the history of synaptic use, others reflect the activity of modulatory neurons that are controlled through neural computations, and still others involve more global measures of neural activity. The molecular machinery synapses use to convey information from one neuron to the next not only plays an essential part in brain function but also is at the basis of processes that are vital to all cells. Because membrane fusion events at synapses are so precisely controlled, synapses offer an especially favorable system in which to study these basic processes. Here, I review some of the recent progress that has been made in understanding both how synaptic strength is regulated and how fundamental cell biological mechanisms are used to accomplish neuronal intercommunication.