LAR-RPTPs: synaptic adhesion molecules that shape synapse development

The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated that LAR-RPTP family members are also involved in diverse synaptic functions, playing a role in synaptic adhesion pathways together with a host of distinct transmembrane proteins and serving as major synaptic adhesion molecules in governing pre- and postsynaptic development, dysfunctions of which may underlie various disorders. This review highlights the emerging role of LAR-RPTPs as synapse organizers in orchestrating synapse development.     

Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation

Neuronal morphology and number of synapses is not static, but can change in response to a variety of factors, a process called synaptic plasticity. These structural and molecular changes are believed to represent the basis for learning and memory, thereby underling both the developmental and activity-dependent remodelling of excitatory synapses. Here, we report that Zn(2+) ions, which are highly enriched within the postsynaptic density (PSD), are able to influence the recruitment of ProSAP/Shank proteins to PSDs in a family member-specific manner during the course of synaptogenesis and synapse maturation. Through selectively overexpressing each family member at excitatory postsynapses and comparing this to shRNA-mediated knockdown, we could demonstrate that only the overexpression of zinc-sensitive ProSAP1/Shank2 or ProSAP2/Shank3 leads to increased synapse density, although all of them cause a decrease upon knockdown. Furthermore, depletion of synaptic Zn(2+) along with the knockdown of zinc-insensitive Shank1 causes the rapid disintegration of PSDs and the loss of several postsynaptic molecules including Homer1, PSD-95 and NMDA receptors. These findings lead to the model that the concerted action of ProSAP/Shank and Zn(2+) is essential for the structural integrity of PSDs and moreover that it is an important element of synapse formation, maturation and structural plasticity.     

Transmission,Development, and Plasticity of Synapses

Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre- and postsynaptic cells communicate to regulate plasticity in response to activity.     

Modeling synaptic transmission of the tripartite synapse

The tripartite synapse denotes the junction of a pre- and postsynaptic neuron modulated by a synaptic astrocyte. Enhanced transmission probability and frequency of the postsynaptic current-events are among the significant effects of the astrocyte on the synapse as experimentally characterized by several groups. In this paper we provide a mathematical framework for the relevant synaptic interactions between neurons and astrocytes that can account quantitatively for both the astrocytic effects on the synaptic transmission and the spontaneous postsynaptic events. Inferred from experiments, the model assumes that glutamate released by the astrocytes in response to synaptic activity regulates store-operated calcium in the presynaptic terminal. This source of calcium is distinct from voltage-gated calcium influx and accounts for the long timescale of facilitation at the synapse seen in correlation with calcium activity in the astrocytes. Our model predicts the inter-event interval distribution of spontaneous current activity mediated by a synaptic astrocyte and provides an additional insight into a novel mechanism for plasticity in which a low fidelity synapse gets transformed into a high fidelity synapse via astrocytic coupling.     

Remodeling of synaptic actin induced by photoconductive stimulation.

Use-dependent synapse remodeling is thought to provide a cellular mechanism for encoding durable memories, yet whether activity triggers an actual structural change has remained controversial. We use photoconductive stimulation to demonstrate activity-dependent morphological synaptic plasticity by video imaging of GFP-actin at individual synapses. A single tetanus transiently moves presynaptic actin toward and postsynaptic actin away from the synaptic junction. Repetitive spaced tetani induce glutamate receptor-dependent stable restructuring of synapses. Presynaptic actin redistributes and forms new puncta that label for an active synapse marker FM5-95 within 2 hr. Postsynaptic actin sprouts projections toward the new presynaptic actin puncta, resembling the axon-dendrite interaction during synaptogenesis. Our results indicate that activity-dependent presynaptic structural plasticity facilitates the formation of new active presynaptic terminals.     

The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity

Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.     

Activity-dependent wiring of the developing hippocampal neuronal circuit

In the developing hippocampus, functional excitatory synaptic connections seem to be recruited from a preformed, initially silent synaptic network. This functional synapse induction requires presynaptic action potentials paired with postsynaptic depolarization, thus obeying Hebb's rule of association. During early postnatal development the hippocampus exhibits an endogenous form of patterned neuronal activity that is driven by GABAergic depolarization. We propose that this recurrent activity promotes the input-specific induction of functional synapses in the CA1 region. Thus, activity-dependent synaptic reorganization in the developing hippocampus appears to be dominated by an active recruitment of new synapses rather than an active elimination of redundant connections.     

The molecular signals that regulate activity-dependent synapse refinement in the brain

The formation of appropriate synaptic connections is critical for the proper functioning of the brain. Early in development, neurons form a surplus of immature synapses. To establish efficient, functional neural networks, neurons selectively stabilize active synapses and eliminate less active ones. This process is known as activity-dependent synapse refinement. Defects in this process have been implicated in neuropsychiatric disorders such as schizophrenia and autism. Here we review the manner and mechanisms by which synapse elimination is regulated through activity-dependent competition. We propose a theoretical framework for the molecular mechanisms of synapse refinement, in which three types of signals regulate the refinement. We then describe the identity of these signals and discuss how multiple molecular signals interact to achieve appropriate synapse refinement in the brain.     

A trace of silence: memory and microRNA at the synapse

Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?     

GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

GABA-mediated synaptic inhibition is crucial in neural circuit operations. In mammalian brains, the development of inhibitory synapses and innervation patterns is often a prolonged postnatal process, regulated by neural activity. Emerging evidence indicates that gamma-aminobutyric acid (GABA) acts beyond inhibitory transmission and regulates inhibitory synapse development. Indeed, GABA(A) receptors not only function as chloride channels that regulate membrane voltage and conductance but also play structural roles in synapse maturation and stabilization. The link from GABA(A) receptors to postsynaptic and presynaptic adhesion is probably mediated, partly by neuroligin-reurexin interactions, which are potent in promoting GABAergic synapse formation. Therefore, similar to glutamate signaling at excitatory synapse, GABA signaling may coordinate maturation of presynaptic and postsynaptic sites at inhibitory synapses. Defining the many steps from GABA signaling to receptor trafficking/stability and neuroligin function will provide further mechanistic insights into activity-dependent development and possibly plasticity of inhibitory synapses.     

Repetitive impulse activity potentiates spontaneous acetylcholine secretion at developing neuromuscular synapses.

The effects of presynaptic impulse activity on the transmitter secretion at developing neuromuscular junctions were examined in Xenopus nerve-muscle cultures. Repetitive suprathreshold stimulation of the presynaptic neuron results in marked potentiation of spontaneous synaptic activity, as shown by whole-cell voltage-clamp recording of synaptic currents in the postsynaptic muscle cell. Our results are consistent with the notion that synaptic efficacy of the developing synapse is potentiated by the presence of electrical activity. Such activity-dependent synaptic modulation enables the early neuronal activity to play a regulatory role during the maturation of synaptic connections.     

BDNF increases synapse density in dendrites of developing tectal neurons in vivo

Neuronal connections are established through a series of developmental events that involve close communication between pre- and postsynaptic neurons. In the visual system, BDNF modulates the development of neuronal connectivity by influencing presynaptic retinal ganglion cell (RGC) axons. Increasing BDNF levels in the optic tectum of Xenopus tadpoles significantly increases both axon arborization and synapse density per axon terminal within a few hours of treatment. Here, we have further explored the mechanisms by which BDNF shapes synaptic connectivity by imaging tectal neurons, the postsynaptic partners of RGCs. Individual neurons were co-labeled with DsRed2 and a GFP-tagged postsynaptic density protein (PSD95-GFP) to visualize dendritic morphology and postsynaptic specializations simultaneously in vivo. Immunoelectron microscopy confirmed that PSD95-GFP predominantly localized to ultrastructurally identified synapses. Time-lapse confocal microscopy of individual, double-labeled neurons revealed a coincident, activity-dependent mechanism of synaptogenesis and axon and dendritic arbor growth, which is differentially modulated by BDNF. Microinjection of BDNF into the optic tectum significantly increased synapse number in tectal neuron dendritic arbors within 24 hours, without significantly influencing arbor morphology. BDNF function-blocking antibodies had opposite effects. The BDNF-elicited increase in synapse number complements the previously observed increase in presynaptic sites on RGC axons. These results, together with the timescale of the response by tectal neurons, suggest that the effects of BDNF on dendritic synaptic connectivity are secondary to its effects on presynaptic RGCs. Thus, BDNF influences synaptic connectivity in multiple ways: it enhances axon arbor complexity expanding the synaptic territory of the axon, while simultaneously coordinating synapse formation and stabilization with individual postsynaptic cells.     

Roles of ubiquitination at the synapse

The ubiquitin proteasome system (UPS) was first described as a mechanism for protein degradation more than three decades ago, but the critical roles of the UPS in regulating neuronal synapses have only recently begun to be revealed. Targeted ubiquitination of synaptic proteins affects multiple facets of the synapse throughout its life cycle; from synaptogenesis and synapse elimination to activity-dependent synaptic plasticity and remodeling. The recent identification of specific UPS molecular pathways that act locally at the synapse illustrates the exquisite specificity of ubiquitination in regulating synaptic protein trafficking and degradation events. Synaptic activity has also been shown to determine the subcellular distribution and composition of the proteasome, providing additional mechanisms for locally regulating synaptic protein degradation. Together these advances reveal that tight control of protein turnover plays a conserved, central role in establishing and modulating synapses in neural circuits.     

Pre- and postsynaptic mechanisms in Hebbian activity-dependent synapse modification

We have used a three compartment tissue culture system that involved two separate populations of cholinergic neurons in the side compartments that converged on a common target population of myotubes in the center compartment. Activation of the axons from one population of neurons produced selective down-regulation of the synaptic inputs from the other neuronal population (when the two inputs innervated the same myotubes). The decrease in heterosynaptic inputs was mediated by protein kinase C (PKC). An activity-dependent action of protein kinase A (PKA) was associated with the stimulated input and this served to selectively stabilize this input. These changes associated with PKA and PKC activation were mediated by alterations in the number of acetylcholine receptors at the neuromuscular junction. These results suggest that neuromuscular electrical activity produces postsynaptic activation of both PKA and PKC, with the latter producing generalized synapse weakening and the former a selective synapse stabilization. Treatment of the neuronal cell body and axon to increase PKC activity by putting phorbal ester (PMA) in the side chamber did not affect synaptic transmission (with or without stimulation). By contrast, PKA blockade in the side compartment did produce an activity-dependent decrease in synaptic efficacy, which was due to a decrease in quantal release of neurotransmitter. Thus, when the synapse is activated, it appears that presynaptic PKA action is necessary to maintain transmitter output.     

Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse

The receptor tyrosine kinase, TrkB, is critical to diverse functions of the mammalian nervous system in health and disease. Evidence of TrkB activation during epileptogenesis in vivo despite genetic deletion of its prototypic neurotrophin ligands led us to hypothesize that a non-neurotrophin, the divalent cation zinc, can transactivate TrkB. We found that zinc activates TrkB through increasing Src family kinase activity by an activity-regulated mechanism independent of neurotrophins. One subcellular locale at which zinc activates TrkB is the postsynaptic density of excitatory synapses. Exogenous zinc potentiates the efficacy of the hippocampal mossy fiber (mf)-CA3 pyramid synapse by a TrkB-requiring mechanism. Long-term potentiation of this synapse is impaired by deletion of TrkB, inhibition of TrkB kinase activity, and by CaEDTA, a selective chelator of zinc. The activity-dependent activation of synaptic TrkB in a neurotrophin-independent manner provides a mechanism by which this receptor can regulate synaptic plasticity.     

The flip side of synapse elimination

The fine tuning of synaptic circuits often requires an activity-dependent phase in which appropriate connections are strengthened and inappropriate connections are eliminated. In this issue of Neuron, Walsh and Lichtman propose a novel "synaptic takeover" mechanism for synapse elimination at the vertebrate NMJ, where withdrawal of one axon is accompanied by expansion of a competing axon into the newly vacated territory.     

Fast and slow excitation of inhibitory cells in the CA3 region of the hippocampus

Pyramidal cells form excitatory synaptic connections with local inhibitory neurons in the hippocampus. This recurrent synapse plays a crucial stabilizing role in the control of hippocampal activity, since it transforms pyramidal cell population. Using a combination of dual recording from presynaptic and postsynaptic cells and anatomical techniques, we show that these synaptic connections often comprise a single site for liberation of excitatory transmitter. The resulting excitatory postsynaptic potentials (EPSCs) have a fast time course and a similar amplitude to miniature EPSCs recorded in tetrodotoxin and cobalt. In contrast, activation of metabotropic glutamate receptors (mGluRs) by transmitter liberated during repetitive activation of these synapses produces an excitation with a much slower time course. In addition to somatodendritic mGluRs, which excite inhibitory cells, a different species of mGluR is present on inhibitory cell terminals. This mGluR is activated by higher concentrations of the agonist t-1-amino-cyclopentyl–1,3-decarboxylate and acts to reduce γ-aminobutyric acid release. mGluRs, thus, have a dual action to enhance and to depress synaptic inhibition in the hippocampus. © 1995 John Wiley & Sons, Inc.     

The legacy of Donald O. Hebb: more than the Hebb synapse

Neuroscientists associate the name of Donald O. Hebb with the Hebbian synapse and the Hebbian learning rule, which underlie connectionist theories and synaptic plasticity, but Hebb's work has also influenced developmental psychology, neuropsychology, perception and the study of emotions, as well as learning and memory. Here, we review the work of Hebb and its lasting influence on neuroscience in honour of the 2004 centenary of his birth.     

Transsynaptic channelosomes: non-conducting roles of ion channels in synapse formation

Recent findings demonstrate that synaptic channels are directly involved in the formation and maintenance of synapses by interacting with synapse organizers. The synaptic channels on the pre- and postsynaptic membranes possess non-conducting roles in addition to their functional roles as ion-conducting channels required for synaptic transmission. For example, presynaptic voltage-dependent calcium channels link the target-derived synapse organizer laminin β2 to cytomatrix of the active zone and function as scaffolding proteins to organize the presynaptic active zones. Furthermore, postsynaptic δ2-type glutamate receptors organize the synapses by forming transsynaptic protein complexes with presynaptic neurexins through synapse organizer cerebellin 1 precursor proteins. Interestingly, the synaptic clustering of AMPA receptors is regulated by neuronal activity-regulated pentraxins, while postsynaptic differentiation is induced by the interaction of postsynaptic calcium channels and thrombospondins. This review will focus on the non-conducting functions of ion-channels that contribute to the synapse formation in concert with synapse organizers and active-zone-specific proteins.     

Synaptic plasticity in learning and memory

Pavlovian conditioning has been considered as one of the principal experimental approaches to understanding such complex brain functions as learning and memory. Use-dependent alterations in synaptic efficacy are believed to form the basis for these functions. The algorithm of synapse modification proposed by D. Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols which were used to reveal the manifestations of Hebb-type plasticity in the synaptic inputs to neocortical and hippocampal neurons. Special attention is focused on long-term modifications of synaptic efficacy in the hippocampus as a possible neuronal mechanism of learning and the role of disinhibition in their development. The effects of various neuromodulators on hippocampal long-term potentiation are considered. It is suggested that along with their involvement in disinhibition processes these substances may control the Hebb-type plasticity through intracellular second messenger systems.