Proteolytic activity,synapse elimination,and the Hebb synapse

The Hebb synapse has been postulated to serve as a mechanism subserving both regulation of synaptic strength in the adult nervous system (long-term potentiation and depression) and developmental activity-dependent plasticity. According to this model, pre- and postsynaptic temporal concordance of activity results in strengthening of connections, while discordant activity results in synapse weakening. Evidence is presented that proteases and protease inhibitors may be involved in modification of synaptic strength. This leads to a modification of the Hebb assumptions, namely that postsynaptic activity results in protease elaboration with a consequent general reduction of synaptic connections to the active postsynaptic element. Further, presynaptic activity, if strong enough, induces local release of a protease inhibitor, such as protease nexin I, which neutralizes proteolytic activity and produces a relative preservation of the active input. This formulation produces many of the effects of the classical Hebbian construction, but the protease/inhibitor model suggests additional specific mechanistic features for activity-dependent plasticity. 1994 John Wiley & Sons, Inc.     

An activity-dependent determinant of synapse elimination in the mammalian brain

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Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

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Co-cultures of inferior olive and cerebellum: Electrophysiological evidence for multiple innervation of Purkinje cells by olivary axons

Slices of inferior olive (IO) and cerebellum were co-cultured for several weeks by means of the roller tube technique. Recordings were carried out intracellularly from Purkinje cells (PCs) which were identified morphologically by intracellular injection of the fluorescent dye Lucifer yellow, or by immunohistochemical stainings with antibodies raised against the 28 kD Ca²⁺-binding protein calbindin. Following stimulation of olivary tissue, an all-or-none full complex spike response was recorded in some PCs consisting of a fast rising spike followed by a depolarizing potential. In other PCs, graded stimulation of the olivary explant induced synaptic potentials which were characterized by step-wise variation in their amplitude and resembled the ones occurring spontaneously. In contrast, only smoothly graded synaptic potentials were observed in cerebellar mono-cultures. These results indicate that some of the PCs in olivo-cerebellar co-cultures are innervated by several olivary neurons.     

Tetanic stimulation and cyclic adenosine monophosphate regulate segregation of presynaptic inputs on a common postsynaptic target neuron in vitro

Previous studies indicated that Aplysia sensory neurons (SNs) compete when reestablishing synapses with a motor cell target (1.7) in vitro. The competition is characterized by a cell number-dependent decrease in the efficacy of each connection, an increase in the elimination of SN varicosities, a reduction in the formation of new SN varicosities, and the segregation of varicosities of each SN to restricted portions of the target axons. The changes do not require spike activity, since both the SNs and L7 do not fire spontaneously. Here, we examined whether adding activity to SNs during the early stages of synapse formation with stimuli known to evoke facilitatory responses in stable SN-L7 connections—tetanic stimulation or increase in intracellular cyclic adenosine monophosphate (cAMP)—would modulate the intrinsic segregatory process. Tetanic stimulation to one SN increased synapse efficacy and the number of varicosities of the stimulated SNs while reducing the functional changes by the nonstimulated SNs in the same cultures. An increase in the stability of preexisting varicosities contributed to the overall increase in varicosities evoked by tetanus. The functional changes evoked by tetanus were not expressed when the same tetanic stimulation was also given to the other SN, or when L7 was hyperpolarized during the tetanus to the SN. Raising cAMP levels in one SN increased synapse efficacy and the rate of new varicosity formation by the injected SNs without affecting the development of the connections formed by the noninjected SNs. These results suggest that different forms of presynaptic and postsynaptic activities in neurons can regulate specific aspects of the competitive process associated with the fine-tuning of connections formed by converging presynaptic inputs. © 1996 John Wiley & Sons, Inc.     

Comparison of fast and slow synaptic terminals in lobster muscle

Summary Synaptic terminals of fast (FCE) and slow (SCE) excitatory neurons were physiologically identified on separate fibres of one muscle, the closer muscle in lobster claws. The innervation by these identified fibers was demonstrated over long distances (7–21 m) by examining serial thin sections at periodic intervals. The ultrastructure of each type of innervation was consistent both qualitatively and quantitatively in two separate samples. The FCE innervation is relatively simple in having consistently small-diameter terminals each forming a single long synapse, with few synaptic vesicles, and little if any postsynaptic apparatus. The SCE innervation is more complex in having larger-diameter but more variable terminals forming several short synapses, with many synaptic vesicles and an extensive postsynaptic apparatus. These differences in the size of the synapses and the number of synaptic vesicles parallel differences in transmitter release and fatigue sensitivity characteristic of the two types of innervation. The degree of elaboration of the postsynaptic apparatus may reflect differences in the amount of transmitter taken up after release. Our data reveal for the first time in a single muscle differences between FCE and SCE innervation previously reported in different muscles and in different species.Supported by grants from NIH (NINCDS) to A.G. Humes and the late Fred Lang and from NSERC and Muscular Dystrophy Assoc. of Canada to C.K. GovindWe thank Lena Hill for her technical expertise and critical evaluation of the study, and Dr. A.G. Humes for providing research facilities     

Synaptic organization of the cabbage looper moth ocellus

Summary Chemical and electronic synapses are present in the ocellar synaptic region of the moth, Trichoplusia ni. The chemical synapses all appear to be of the conventional type. Four different chemical synaptic contacts were observed: Receptor cell axons presynaptic to receptor cell axons, receptor cell axons presynaptic to 1st order interneurons, 1st order interneurons presynaptic to receptor cell axons, and 1st order interneurons presynaptic to 1st order interneurons. Two different types of contact made by electronic synapes were observed: Contacts between receptor cell axons and 1st order interneurons, and contacts between 1st order interneurons. The significance of this synaptic arrangement for the generation of on and off responses in the 1st order interneurons is discussed.Supported by NSF Grant BMS 75-07645 and by the VPI & SU Research Division     

Ionotropic Receptors as a Driving Force behind Human Synapse Establishment

The origin of nervous systems is a main theme in biology and its mechanisms are largely underlied by synaptic neurotransmission. One problem to explain synapse establishment is that synaptic orthologs are present in multiple aneural organisms. We questioned how the interactions among these elements evolved and to what extent it relates to our understanding of the nervous systems complexity. We identified the human neurotransmission gene network based on genes present in GABAergic, glutamatergic, serotonergic, dopaminergic, and cholinergic systems. The network comprises 321 human genes, 83 of which act exclusively in the nervous system. We reconstructed the evolutionary scenario of synapse emergence by looking for synaptic orthologs in 476 eukaryotes. The Human–Cnidaria common ancestor displayed a massive emergence of neuroexclusive genes, mainly ionotropic receptors, which might have been crucial to the evolution of synapses. Very few synaptic genes had their origin after the Human–Cnidaria common ancestor. We also identified a higher abundance of synaptic proteins in vertebrates, which suggests an increase in the synaptic network complexity of those organisms.     

Identifying roles for neurotransmission in circuit assembly: insights gained from multiple model systems and experimental approaches

In the adult nervous system, chemical neurotransmission between neurons is essential for information processing. However, neurotransmission is also important for patterning circuits during development, but its precise roles have yet to be identified, and some remain highly debated. Here, we highlight viewpoints that have come to be widely accepted or still challenged. We discuss how distinct techniques and model systems employed to probe the developmental role of neurotransmission may reconcile disparate ideas. We underscore how the effects of perturbing neurotransmission during development vary with model systems, the stage of development when transmission is altered, the nature of the perturbation, and how connectivity is assessed. Based on findings in circuits with connectivity arranged in layers, we raise the possibility that there exist constraints in neuronal network design that limit the role of neurotransmission. We propose that activity-dependent mechanisms are effective in refining connectivity patterns only when inputs from different cells are close enough, spatially, to influence each other's outcome.     

ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder

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Synaptic oligomeric tau in Alzheimer’s disease — A potential culprit in the spread of tau pathology through the brain

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Drosophila synaptotagmin I null mutants survive to early adulthood

Summary: Synaptotagmin is a synaptic vesicle protein required for efficient neurotransmitter release, yet its exact role in the synaptic vesicle cycle is unclear. Drosophila presents an ideal organism for studies aimed at determining the in vivo functions of proteins. However, synaptotagmin studies have been limited by the early (embryonic or first instar) lethality previously reported for Drosophila synaptotagmin I null (syt^null) mutants. Here we report a new culturing technique that enhances survival of severely uncoordinated mutants thereby permitting Drosophila syt^null mutants to survive through early adulthood. We examined synapses in syt^null third instar larvae by electrophysiology and found that they exhibit severely decreased and asynchronous evoked neurotransmitter release, as well as an increased rate of spontaneous neurotransmitter release, as previously seen in first instar syt^null larvae. The ability to examine severe synaptotagmin mutants as third instar larvae, a stage where electrophysiological and morphological analyses are more easily accomplished, will facilitate structure/function studies. genesis 31:30–36, 2001. © 2001 Wiley‐Liss, Inc.     

幼年大鼠视皮层神经元对闪光刺激的反应特性

哺乳动物视觉系统的发育延续到出生后,大鼠出生后 3~5 周是视觉系统发育的关键期 . 在关键期中,视皮层的兴奋性和抑制性突触连接逐渐成熟,形成有效的皮层内回路 . 为了观察发育关键期大鼠视皮层神经元的反应特性与成年大鼠的异同,使用胞外单细胞记录的方法对比研究了幼年和成年大鼠对闪光刺激的视觉反应特性 . 结果显示：与成年大鼠相比较,幼年大鼠视皮层神经元对持续闪光刺激显示出更强的适应性,对光刺激的诱发放电频率更低,而在没有光刺激时的自发放电频率更高,从而导致信噪比更低 . 这一结果表明,幼年大鼠视皮层对连续刺激的反应能力下降,对信号的分辨能力也更弱,其原因可能是兴奋性突触和抑制性突触发育的不同步所致 .     

Synaptic scaffolding molecule (S-SCAM) membrane-associated guanylate kinase with inverted organization (MAGI)-2 is associated with cell adhesion molecules at inhibitory synapses in rat hippocampal neurons

Synaptic scaffolding molecule (S-SCAM) is a synaptic protein, which harbors five or six PSD-95/Discs large/ZO-1 (PDZ), a guanylate kinase and two WW domains. It interacts with NMDA receptor subunits, neuroligin and beta-catenin, and is involved in the accumulation of neuroligin at excitatory synapses. In this study, we have demonstrated S-SCAM is localized at inhibitory synapses in rat primary cultured hippocampal neurons. We have identified beta-dystroglycan (beta-DG) as a binding partner for S-SCAM at inhibitory synapses. WW domains of S-SCAM bind to three sequences of beta-DG. We have also revealed that S-SCAM can interact with neuroligin 2, which is known to be exclusively localized at inhibitory synapses. The WW domains and the second PDZ domain of S-SCAM are involved in the interaction with neuroligin 2. Beta-DG, neuroligin 2 and S-SCAM form a tripartite complex in vitro. Neuroligin 2 is detected in the immunoprecipitates by anti-beta-DG antibody from rat brain. S-SCAM, beta-DG and neuroligin 2 are partially co-localized in rat hippocampal neurons. These data suggest that S-SCAM is associated with beta-DG and neuroligin 2 at inhibitory synapses, and functions as a linker between the dystrophin glycoprotein complex and the neurexin-neuroligin complex.     

pH changes in the invaginating synaptic cleft mediate feedback from horizontal cells to cone photoreceptors by modulating Ca2+ channels

Feedback from horizontal cells (HCs) to cone photoreceptors plays a key role in the center-surround-receptive field organization of retinal neurons. Recordings from cone photoreceptors in newt retinal slices were obtained by the whole-cell patch-clamp technique, using a superfusate containing a GABA antagonist (100 microM picrotoxin). Surround illumination of the receptive field increased the voltage-dependent calcium current (ICa) in the cones, and shifted the activation voltage of ICa to negative voltages. External alkalinization also increased cone ICa and shifted its activation voltage toward negative voltages. Enrichment of the pH buffering capacity of the extracellular solution increased cone ICa, and blocked any additional increase in cone ICa by surround illumination. Hyperpolarization of the HCs by a glutamate receptor antagonist-augmented cone ICa, whereas depolarization of the HCs by kainate suppressed cone ICa. From these results, we propose the hypothesis that pH changes in the synaptic clefts, which are intimately related to the membrane voltage of the HCs, mediate the feedback from the HCs to cone photoreceptors. The feedback mediated by pH changes in the synaptic cleft may serve as an additional mechanism for the center-surround organization of the receptive field in the outer retina.     

Adhesions ring: a structural comparison between podosomes and the immune synapse

Podosomes and the immune synapse are integrin-mediated adhesive structures that share a common ring-like morphology. Both podosomes and immune synapses have a central core surrounded by a peripheral ring containing talin, vinculin and paxillin. Recent progress suggests significant parallels between the regulatory mechanisms that contribute to the formation of these adhesive structures. In this review, we compare the structures, functions and regulation of podosomes and the immune synapse.     

C-terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3

Synapses are specialized contact sites mediating communication between neurons. Synaptogenesis requires the specific assembly of protein clusters at both sides of the synaptic contact by mechanisms that are barely understood. We studied the synaptic targeting of multi-domain proteins of the ProSAP/Shank family thought to serve as master scaffolding molecules of the postsynaptic density. In contrast to Shank1, expression of green-fluorescent protein (GFP)-tagged ProSAP1/Shank2 and ProSAP2/Shank3 deletion constructs in hippocampal neurons revealed that their postsynaptic localization relies on the integrity of the C-termini. The shortest construct that was perfectly targeted to synaptic sites included the last 417 amino acids of ProSAP1/Shank2 and included the C-terminal sterile alpha motif (SAM) domain. Removal of 54 residues from the N-terminus of this construct resulted in a diffuse distribution in the cytoplasm. Altogether, our data delineate a hitherto unknown targeting signal in both ProSAP1/Shank2 and ProSAP2/Shank3 and provide evidence for an implication of these proteins and their close homologue, Shank1, in distinct molecular pathways.