Ampa Receptor Transport

Due to the highly dynamic nature of AMPA receptors as a mechanism of synaptic plasticity64-66, there exists a wealth of studies which focus on their exo-and endocytosis at mature synapses (see Chapters 22-24). A number of studies suggest that similar mechanisms governing the activity-dependent insertion of AMPA receptors may also be occurring during development8,67,68. AMPA receptors have long been shown to interact directly with NSF and a and P-SNAPs69. These proteins form part of the exocytic...

Complex Assembly And Clustering Of Synaptic Proteins

Recent studies revealed that PDZ domain-containing scaffolding proteins serve an important role in clustering of diverse molecules into large complexes3. The membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins is of central importance in regulation of protein clustering at the synapse. MAGUKs are defined by the presence of a domain homologous to the yeast guanylate kinase (GK) domain, which is catalytically inactive. The GK domain is preceded by an Src-homology-3 (SH3)...

Summary Of Fmrp Proposed Mechanism Of Action

FMRP seems to have a number of functions in the adult nervous system, and it is highly expressed in neurons where one of its functions is to transport and translate mRNAs38,39. Quite possibly the most important feature of FMRP is it's role in mRNP complexes. In the nucleus, FMRP can bind to mRNA, forming a messenger ribonucleoprotein, or mRNP. Via a nuclear export signal (NES), FMRP can leave the nucleus and attach to an anterograde motor protein, with its mRNA still bound. The mRNA and FMRP...

Genetic Tests of the Agrin Hypothesis

The agrin hypothesis has also endured in vivo testing using genetic approaches in mice. Mice that lack agrin die at birth with nonfunctional NMJs10. During embryonic mouse development, motor neurons contact muscle fibers at approximately embryonic day 12-13 (E12-13). Examination of NMJs as early as E15 reveals that postsynaptic differentiation is nearly absent in mice lacking agrin. This phenotype was initially described in mice in which the nervous-system-specific exons encoding the Z+...

Postsynaptic Transport Packets

To understand the molecular methods by which synapse formation occurs, it is critical to know the mechanisms by which all the synaptic components can possibly arrive at a newly forming synapse. Methods of trafficking can range from diffusion through the cytoplasm or in the plasma membrane to exo endocytic cycling between bouts of transport along microtubules. In the case of the post-synaptic density (PSD) of glutamatergic synapses, it appears that many of the necessary proteins arrive...

Structure Of Cadherins And Binding Interactions

Cadherins mediate calcium dependent, mostly homophilic adhesion. They were first identified in vertebrates, but the family is evolutionarily conserved and members can be found in echinoderms, arthropods, and chordates. Between phyla, there is substantial structural diversity, but cadherins have in common a cadherin domain a 110 amino acid sequence that is usually one of several tandem repeats separated by a calcium-binding domain. Current estimates indicate that the cadherin superfamily has as...

Nmda Receptor Trafficking

In contrast to the cytosolic protein PSD-95, the localization and trafficking of transmembrane proteins, such as the NMDA receptor, is intrinsically more complicated. Levels of complication are not only provided by synthesis and processing in the endoplasmic reticulum (ER) and Golgi apparatus, but also by the possibility of both vesicular trafficking and plasma membrane diffusion. At the level of the ER, the trafficking of the NMDA receptor is highly regulated. As with other receptor complexes,...

Neurotrophin Signaling

Neuronal activity controls the synthesis and secretion of neurotrophins during critical periods (CPs) of synaptic development and remodeling1-3. Cumulative evidence suggests that neurotrophins regulate structure and function of synapses, both pre- and postsynaptically4-6. These results make neurotrophins particularly attractive candidates as regulators of synaptogenesis. Nevertheless, studies of neurotrophic regulation of synaptogenesis are still at a descriptive stage, and relatively little is...

Shortinterval Imaging Of Filopodial Motility

Imaging growing dendrites using short intervals ranging from seconds to hours reveals a remarkable level of motility present in immature dendritic arbors. The majority of this motility is associated with short protrusions that rapidly extend and retract from growing dendrites12-15'19'20'26. Over short periods of seconds to minutes, these short protrusions can emerge de novo from existing dendrites, rapidly extend, retract, and disappear (Figure 20.2). These short (usually less than 10 im),...

Role Of Neuroligin Binding To Neurexins In Synaptic Organization

Richard Fairless, Carsten Reissner, and Markus Missler* The complex formed by the synaptic cell adhesion molecules neuroligin and P-neurexin has been implicated in synaptogenesis due to the molecular asymmetry of their heterophilic binding, reflecting the asymmetric nature of the synapse. During the past 5 years, their role in synapse formation has been explored in vitro, yielding exciting, though sometimes conflicting results. In this chapter, we focus on the biochemical and functional aspects...

Increases in the Number of Multiple Synapse Boutons Associated with Learning and Memory

Studies reviewed above indicate that learning of a new behavior is typically accompanied by synaptogenesis in a learning-relevant region of the mammalian brain, which is manifested by an increase in the number of synapses. Another ultrastructural synaptic alteration involving synaptogenesis is multiple-synapse bouton (MSB) formation, which is characteristic of various forms of plasticity (reviewed in 26). Each MSB establishes separate synaptic contacts with two or more discrete postsynaptic...

Evidence For A Learninginduced Addition Of Synapses

Synapses are the primary link between neurons and have both presynaptic and postsynaptic components, separated by a small space called the synaptic cleft, all of which can be seen easily in osmium-fixed tissue at the electron microscopic level. The presynaptic component comprises a vesicle-filled axon terminal, with a small number of vesicles fused to or docked near the presynaptic membrane, and a very thin layer of electron-dense material immediately adjacent to the synaptic cleft. The...

Axonal Pathfinding Versus Synaptic Cell Adhesion

The specificity of synaptic connections is established by two consecutive processes axonal pathfinding and synaptic cell adhesion10. A simple consideration shows that of these two processes, axonal pathfinding is more important than synaptic cell adhesion, although obviously both are essential. This consideration is that synaptic cell adhesion can only operate at a distance of 100 nm, which even on the scale of the densely packed neuropil is a very short distance. Whereas over short distances...

Introduction

Synaptic transmission between neurons in a circuit is the fundamental organizing principle of brain function. It is generally assumed, therefore, that disruptions in the formation, patterning, or maintenance of synapses underlie a wide range of debilitating neurological and psychiatric disorders. As tautologous as this assumption may be, its usefulness for understanding and, eventually, treating such disorders will require identification of the molecules that control synapse development in the...

The Shank And Homer Families

The Shank and Homer protein families are two major components of the PSD that directly interact with each other. Shank, also known as proline-rich synapse-associated protein (ProSAP), somatostatin receptor interacting protein (SSTRIP), cortactin-binding protein (cortBP), Synamon and Spank, is a large scaffold protein whose multidomain organization consists of an ankyrin repeat near the N-terminal, followed by an SH3, a PDZ domain, a long proline-rich region, and a sterile alpha motif domain...

Molecules At The Synapse In Control Of Synaptonuclear Signaling

Several studies in recent years have shown that it is not the increase of intracellular Ca2+ levels per se that leads to activation of gene expression and that it is therefore an open question of what type of Ca2+ signal is needed for activity-dependent transcriptional regulation. The local activation of signaling pathways to the nucleus by plasma membrane Ca2+ channels requires the concerted action of many proteins that are supposed to be present in highly organized macromolecular complexes...

Synaptic Target Recognition

Selecting synaptic partners is a crucial step in neural circuit formation. Synapses are formed in vivo at specific locations, in part, under the control of target recognition molecules. Evidence shows that target selection is mediated not by a point-to-point system, but rather a combinatorial system. Localized attractants, repellants, and stabilization molecules act in combination to create precise neuromuscular contacts essential for muscle function. 5.1.1. Localized Attraction and NMJ...

Changes In Brain Anatomy And The Synapse

Humans with FXS do not show gross cortical abnormalities and have normal brain weights. In some patients there is ventricular enlargement and an increase in hippocampal volumes. MRI studies indicate that the posterior vermis of the cerebellum is decreased and that the size of the caudate nucleus and hippocampus is increased. A diminished white-to-gray matter ratio was also observed in the same study27. The volumes of the cerebellum, caudate nucleus, and the size of the ventricles correlates...

The Scope Of The Synapse Formation Problem

The brain contains more than 1011 neurons, each of which forms and receives many synapses - from a few hundred to more than 100,000. Neurons fall into different types and subtypes that are defined by a characteristic pattern of synaptic connectivity. Here, the 'pattern of synaptic connectivity' refers to which downstream target neurons a neuron forms synaptic contacts with, and which upstream neurons in turn form synapses on a particular neuron. Moreover, the pattern of synaptic connectivity...

Ampa Receptor Endocytosis And Removal From Synapses

The controlled endocytic removal of AMPARs from synapses is as important for synaptic function and plasticity as the delivery of new AMPARs. Similar to the constitutive and regulated pathways for synaptic delivery, there are also constitutive and regulated pathways for the trafficking of AMPARs out of synapses. The continuous movement of receptors from the synaptic membrane into extrasynaptic compartments was originally hypothesized from the fast run-down of AMPAR-mediated synaptic transmission...

Postsynaptic Dysfunction

Morphological and Gross Membrane Alterations Altered cellular morphology is well characterized in human HD tissue, consisting of increased dendritic complexity, as well as spine number and size in moderate HD grades, and truncated, swollen dendritic processes with marked spine loss in advanced cases42. Across many of the HD mouse models, reductions in brain volume and weight are observed when little or no cell death is seen, a finding possibly accounted for by altered cellular morphology,...

Dendritogenesis And Synaptogenesis

Evidence for a relationship between glutamatergic afferent innervation and dendrite growth, and coincidence of developmental periods of maximal dendritogenesis and activity-dependent synaptogenesis14 leaves the question of what is the relationship between synaptogenesis and dendritic growth. In rat cortex, the majority of dendrite growth occurs in the first 3 postnatal weeks and closely parallels the time course of afferent innervation. Likewise, in the cerebellum, Purkinje neuron dendritic...

Animal Models Of Depression

No animal model is entirely comparable to the human disease, this is particularly true for psychiatric diseases which are mainly perceived subjectively and expressed verbally. However, it is possible to model many aspects of depression in rodents. Screening paradigms like the Porsolt swim test or the tail suspension test are in a strict sense not animal models of depression because they do not induce long-lasting behavioral changes comparable to human depression in the animals and the...

Info

Confocal microscopy of the rat hippocampus (Figure 26.1 Colorplate 12) also indicates that in general, Cx I is colocalized with the vesicular GABA transporter, while Cx II colocalizes with the vesicular glutamate transporter. Figure 26.1. Confocal Microscopy of Presynaptic Proteins in Rat Hippocampus. All images from the granule cell layer with the exception of the lower left panel obtained from the mossy fiber terminal zone. These images largely support the colocalization of complexin I with...

Changes In Other Molecular Markers In Schizophrenia

While the focus of the present review is on the relationship between presynaptic proteins and neuropsychiatric disorders, this represents an analysis at just one level of these complex diseases. In the case of schizophrenia, there is also substantial interest at the neural circuit level. In particular, there has been recent interest in the nature of inhibitory circuits within the dorsolateral prefrontal cortex (DLPFC), and how alterations in these circuits may lead to cognitive deficits...

Ampar Endocytosis In

Structurally, AMPARs are presumed to be heteropentameric structures assembled by combining homologous subunits. The current topology model suggests that each AMPAR subunit (GluR) consists of three transmembrane regions, MD1, MD3, and MD4, (MD, membrane domain), and a re-entrant membrane segment corresponding to MD2. The major intracellular carboxyl-terminal (CT) region contains potential sites for protein phosphorylation and binding motifs for GluR-interacting proteins, including adaptor...

Snap25 And Schizophrenia

Presynaptic Localization of SNAP-25 SNAP-25 is one of the three core presynaptic proteins that combine to form the SNARE complex. Structural members of the SNAP-25 protein family contribute two of the four alpha helices that compose the SNARE complex, which is necessary for Ca2+-triggered exocytic transmitter release. The first characterized SNAP-25 proteins were the two isoforms SNAP-25A and SNAP-25B, which represent highly homologous proteins that differ by only nine amino acids44....

Biochemical Aspects Of The Interaction Between Neurexin And Neuroligin

The binding between the extracellular domains of neuroligin and P-neurexin is characterized by its dependence upon alternative splicing of both molecules, the glycosylation and dimerization of neuroligin, and the presence of Ca2+ ions. Intracellularly, both transmembrane proteins interact with different binding partners in the pre- and postsynaptic compartments, respectively. Neurexins form a large family of cell-surface proteins7,8. Each of the three vertebrate neurexin genes has two...

Potential Utility Of Interference Peptides In The Treatment Of Drug Addiction

Given the involvement of the NAc in the maintenance of behavioral sensitization and its association with enhanced LTD, LTD in the NAc may be a critical substrate for the expression of sensitization. LTD observed in the hippocampal CA1 region and LTD in the NAc in animals sensitized to repeated exposure to drugs such as amphetamine or cocaine seem to share a common mechanism, manifested as a consequence of specific reduction of AMPARs, possibly by facilitated endocytosis of AMPARs24. Peptides...

Myosin Function In Dendritic Spines

Dendritic spines are unique compartments because they contain little, if any microtubules, but are rich in actin filaments. Organelles, such as smooth endo-plasmic reticulum and ribososmes, as well as a large number of proteins that form the postsynaptic density need to be transported into dendritic spines. There is considerable evidence that these compartments undergo structural changes that are dependent upon actin filaments and neuronal activity40. Whether transport plays a role for such...

Interference Peptides A Novel Therapeutic Approach Targeting Synaptic Plasticity In Drug Addiction

Phillips, Yu Tian Wang, and Tak Pan Wong Synaptic plasticity at excitatory synapses has been proposed as the cellular substrate of information processing and memory formation in the brain under both physiological and pathological conditions, including addiction. There is a growing body of evidence that implicates long-term depression LTD , particularly in the nucleus accumbens NAc , as a potential mediator of drug-induced neural plasticity. In animals, behavioral...

Dendritic Spine Structure

The functions and properties of a synapse localized on a dendritic spine are probably largely dependent and directly controlled by the shape, structure, and molecular composition of the spine itself, and also the number and shape of dendritic spines are controlled by synaptic activity. One finding that supports the importance of spine shape and number in cognitive functions is the fact that both parameters are altered in various genetic diseases involving mental retardation, although it is not...

Ampa Receptor Transport Along The Cytoskeleton In Dendrites And In Spines

The long-range dendritic trafficking of AMPARs depends on the microtubular cytoskeleton that runs along dendritic shafts. This can be demonstrated by monitoring AMPAR dendritic trafficking in neurons in which the tubulin cytoskeleton is destabilized pharmacologically. As shown in Figure 24.1 Colorplate 11 , incubation with a low concentration of vincristine a microtubule destabilizer impairs the dendritic transport of newly synthesized green fluorescence protein GFP -tagged AMPARs, to the point...

Agrins Postsynaptic Mechanism

The postsynaptic signal transduction mechanisms for agrin have also been examined Figure 1.3 . Muscle specific kinase MuSK is a receptor tyrosine kinase that is essential for agrin signal transduction16. Mice that lack MuSK show a phenotype similar to agrin-knockout mice, with a complete lack of AChR clustering even more severe than the agrin-knockout phenotype and a similar presynaptic phenotype17. In addition, muscle fibers cultured from MuSK-knockout mice do not respond to agrin, and agrin...

The Plasma Membrane At Active Zones

Munc13 Syntaxin

The active zone plasma membrane must be designed i to mediate exocytic release of neurotransmitter from SVs, ii to allow the local entry of calcium ions from the extracellular space to trigger transmitter release, and iii to organize trans-synaptic cell adhesion via membrane proteins. In fact, it does contain the target membrane SNARE proteins syntaxin and SNAP25, which by binding to the SV transmembrane protein VAMP mediate SV exocytosis5. Of note, syntaxin and SNAP25 are located all over the...

Contributors

Anderson, Mount Sinai School of Medicine, New York, NY, 10029, USA Alasdair M. Barr, University of British Columbia, Vancouver, BC, V5Z 1L8, Canada Deanna L. Benson, Mount Sinai School of Medicine, New York, NY, 10029, USA Thomas Biederer, Yale University, New Haven CT, 06520-8220, USA Karen Brebner, University of British Columbia, Vancouver, BC, V6T 2A1, Canada Robert W. Burgess, Jackson Laboratory, Bar Harbor, ME, 04609, USA Daniel Choquet, Universit Bordeaux, Bordeaux, 33077, France...