The actin cytoskeleton and synaptic plasticity. (original) (raw)
Neural plasticity, 2016
Disruption of synaptic function at excitatory synapses is one of the earliest pathological changes seen in wide range of neurological diseases. The proper control of the segregation of neurotransmitter receptors at these synapses is directly correlated with the intact regulation of the postsynaptic cytoskeleton. In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment. Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization. We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology.
Fine structure of synapses on dendritic spines
Frontiers in Neuroanatomy, 2014
Camillo Golgi's "Reazione Nera" led to the discovery of dendritic spines, small appendages originating from dendritic shafts. With the advent of electron microscopy (EM) they were identified as sites of synaptic contact. Later it was found that changes in synaptic strength were associated with changes in the shape of dendritic spines. While live-cell imaging was advantageous in monitoring the time course of such changes in spine structure, EM is still the best method for the simultaneous visualization of all cellular components, including actual synaptic contacts, at high resolution. Immunogold labeling for EM reveals the precise localization of molecules in relation to synaptic structures. Previous EM studies of spines and synapses were performed in tissue subjected to aldehyde fixation and dehydration in ethanol, which is associated with protein denaturation and tissue shrinkage. It has remained an issue to what extent fine structural details are preserved when subjecting the tissue to these procedures. In the present review, we report recent studies on the fine structure of spines and synapses using high-pressure freezing (HPF), which avoids protein denaturation by aldehydes and results in an excellent preservation of ultrastructural detail. In these studies, HPF was used to monitor subtle fine-structural changes in spine shape associated with chemically induced long-term potentiation (cLTP) at identified hippocampal mossy fiber synapses. Changes in spine shape result from reorganization of the actin cytoskeleton. We report that cLTP was associated with decreased immunogold labeling for phosphorylated cofilin (p-cofilin), an actin-depolymerizing protein. Phosphorylation of cofilin renders it unable to depolymerize F-actin, which stabilizes the actin cytoskeleton. Decreased levels of p-cofilin, in turn, suggest increased actin turnover, possibly underlying the changes in spine shape associated with cLTP. The findings reviewed here establish HPF as an appropriate method for studying the fine structure and molecular composition of synapses on dendritic spines. Citation: Frotscher M, Studer D, Graber W, Chai X, Nestel S and Zhao S (2014) Fine structure of synapses on dendritic spines. Front. Neuroanat. 8:94.
The Journal of cell …, 1995
Synapsin I is a synaptic vesicle-associated protein which inhibits neurotransmitter release, an effect which is abolished upon its phosphorylation by Ca2÷/calmodulin-dependent protein kinase II (CaM kinase ]I). Based on indirect evidence, it was suggested that this effect on neurotransmitter release may be achieved by the reversible anchoring of synaptic vesicles to the actin cytoskeleton of the nerve terminal. Using video-enhanced microscopy, we have now obtained experimental evidence in support of this model: the presence of dephosphorylated synapsin I is necessary for synaptic vesicles to bind actin; synapsin I is able to promote actin polymerization and bundling of actin filaments in the presence of synaptic vesicles; the ability to cross-link synaptic vesicles and actin is
Induction of Spine Growth and Synapse Formation by Regulation of the Spine Actin Cytoskeleton
Neuron, 2004
Howard Hughes Medical Institute al., 2003); (3) emergence and retraction of spines over Cold Spring Harbor Laboratory longer times (Maletic-Savatic et al., 1999; Engert and Cold Spring Harbor, New York 11724 Bonhoeffer, 1999; Trachtenberg et al., 2002; Grutzendler 2 Institut de Biologie Cellulaire et Morphologie et al., 2002). Little is known about the structure of the Université de Lausanne spine actin cytoskeleton. Spine actin is mostly in fila-Rue du Bugnon 9 mentous form, and the time constant of actin turnover CH 1005, Lausanne is on the order of 40 s (Star et al., 2002). This rapid rate Switzerland suggests that actin turnover underlies the small, rapid spine shape changes. The relationships between the Duke University Medical Center cytoskeleton and spine growth and retraction are Durham, North Carolina 27710 poorly understood. Extrinsic and intrinsic signals likely both influence the rate of motility of dendritic spines. Extracellular signaling Summary molecules can affect the size, shape, or density of dendritic spines (Halpain et al., 1998; McKinney et al., 1999; We explored the relationship between regulation of Ethell et al., 2001; Wong and Wong, 2001; Penzes et al., the spine actin cytoskeleton, spine morphogenesis, 2003). In addition, manipulation of many intrinsic spine and synapse formation by manipulating expression of proteins has been demonstrated to influence spine size, the actin binding protein NrbI and its deletion mutants. shape, or density (Hayashi and Shirao, 1999; Pak et al., In pyramidal neurons of cultured rat hippocampal 2001; Penzes et al., 2001; Sala et al., 2001; Ackermann slices, NrbI is concentrated in dendritic spines by bindand Matus, 2003; Hering and Sheng, 2003; Meng et al., ing to the actin cytoskeleton. Expression of one NrbI 2003; Murai et al., 2003; Pak and Sheng, 2003; Passafaro deletion mutant, containing the actin binding domain, et al., 2003; Sala et al., 2003); one common theme has dramatically increased the density and length of denbeen the involvement of the Rho family GTPases as dritic spines with synapses. This hyperspinogenesis downstream effectors on the actin cytoskeleton (Nakawas accompanied by enhanced actin polymerization yama et al., 2000; Tashiro et al., 2000; Luo, 2002; Ishiand spine motility. Synaptic strengths were reduced to kawa et al., 2003; Govek et al., 2004). Yet it remains compensate for extra synapses, keeping total synaptic unclear how each protein affects the spine actin cyinput per neuron constant. Our data support a model toskeleton and how these effects are transduced into in which synapse formation is promoted by actin-powchanges in spine size, shape, or density. ered motility. NeurabinI (NrbI; Nakanishi et al., 1997) and Spinophilin/NeurabinII (NrbII; Allen et al., 1997; Satoh et al., 1998) Introduction are two related proteins with roles in spine morphogenesis. Knockouts of NrbII show increased spine densities Motility of spines may facilitate synapse formation and during development (Feng et al., 2000), and expression synaptic plasticity (reviewed by Bonhoeffer and Yuste, of NrbI in cultured cells causes filopodial outgrowth (Oli-2002). Spines are highly dynamic during development ver et al., 2002). Both proteins contain N-terminal actin both in vitro (Dailey and Smith, 1996; Dunaevsky et al., binding domains, PP1 binding domains, PDZ domains, 1999) and in vivo (Lendvai et al., 2000; Majewska and and C-terminal coiled-coil domains. The coiled-coil do-Sur, 2003). Periods of high motility coincide with synmain supports homodimerization as well as heterodiapse formation, and it has been suggested that dendritic merization of NrbI/NrbII (MacMillan et al., 1999; Oliver motility is important for the establishment of synaptic et al., 2002). Both proteins have been shown to bind connections (Ziv and Smith, 1996). In fact, sensory depri-F-actin and to promote F-actin crosslinking (Nakanishi vation paradigms that decrease spine motility also diset al., 1997; Satoh et al., 1998). rupt formation of appropriate synaptic circuits (Lendvai Here we used NrbI and NrbI deletion mutants to exet al., 2000)
Journal of Neurophysiology, 2019
The precise patterns of neuronal assembly during development determine all functional outputs of a nervous system; these may range from simple reflexes to learning, memory, cognition, etc. To understand how brain functions and how best to repair it after injury, disease, or trauma, it is imperative that we first seek to define fundamental steps mediating this neuronal assembly. To acquire the sophisticated ensemble of highly specialized networks seen in a mature brain, all proliferated and migrated neurons must extend their axonal and dendritic processes toward targets, which are often located at some distance. Upon contact with potential partners, neurons must undergo dramatic structural changes to become either a pre- or a postsynaptic neuron. This connectivity is cemented through specialized structures termed synapses. Both structurally and functionally, the newly formed synapses are, however, not static as they undergo consistent changes in order for an animal to meet its behavi...
The presynaptic cytomatrix of brain synapses
Cellular and Molecular Life Sciences, 2001
Synapses are principal sites for communica-proteins, including RIM, Bassoon, Piccolo/Aczonin and Munc-13, have been identified, which are specifically tion between neurons via chemical messengers called neurotransmitters. Neurotransmitters are released from localized at the active zone and thus are putative molecpresynaptic nerve terminals at the active zone, a re-ular components of the CAZ. This review will summastricted area of the cell membrane situated exactly op-rize our present knowledge about the structure and function of these CAZ-specific proteins. Moreover, we posite to the postsynaptic neurotransmitter reception apparatus. At the active zone neurotransmitter-contain-will review our present view of how the exocytotic and ing synaptic vesicles (SVs) dock, fuse, release their con-endocytic machineries at the site of neurotransmitter tent and are recycled in a strictly regulated manner. The release are linked to and organized by the presynaptic cytoskeletal matrix at the active zone (CAZ) is thought cytoskeleton. Finally, we will summarize recent progress that has been made in understanding how active zones to play an essential role in the organization of this SV cycle. Several multi-domain cytoskeleton-associated are assembled during nervous system development.
Cell adhesion, the backbone of the synapse: "vertebrate" and "invertebrate" perspectives
Cold Spring Harbor perspectives in biology, 2009
Synapses are asymmetric intercellular junctions that mediate neuronal communication. The number, type, and connectivity patterns of synapses determine the formation, maintenance, and function of neural circuitries. The complexity and specificity of synaptogenesis relies upon modulation of adhesive properties, which regulate contact initiation, synapse formation, maturation, and functional plasticity. Disruption of adhesion may result in structural and functional imbalance that may lead to neurodevelopmental diseases, such as autism, or neurodegeneration, such as Alzheimer's disease. Therefore, understanding the roles of different adhesion protein families in synapse formation is crucial for unraveling the biology of neuronal circuit formation, as well as the pathogenesis of some brain disorders. The present review summarizes some of the knowledge that has been acquired in vertebrate and invertebrate genetic model organisms.
Control of Synapse Structure and Function by Actin and Its Regulators
Cells
Neurons transmit and receive information at specialized junctions called synapses. Excitatory synapses form at the junction between a presynaptic axon terminal and a postsynaptic dendritic spine. Supporting the shape and function of these junctions is a complex network of actin filaments and its regulators. Advances in microscopic techniques have enabled studies of the organization of actin at synapses and its dynamic regulation. In addition to highlighting recent advances in the field, we will provide a brief historical perspective of the understanding of synaptic actin at the synapse. We will also highlight key neuronal functions regulated by actin, including organization of proteins in the pre- and post- synaptic compartments and endocytosis of ion channels. We review the evidence that synapses contain distinct actin pools that differ in their localization and dynamic behaviors and discuss key functions for these actin pools. Finally, whole exome sequencing of humans with neurode...
The structure and function of actin cytoskeleton in mature glutamatergic dendritic spines
Brain Research, 2014
Dendritic spines are actin-rich protrusions from the dendritic shaft, considered to be the locus where most synapses occur, as they receive the vast majority of excitatory connections in the central nervous system (CNS). Interestingly, hippocampal spines are plastic structures that contain a dense array of molecules involved in postsynaptic signalling and synaptic plasticity. Since changes in spine shape and size are correlated with the strength of excitatory synapses, spine morphology directly reflects spine function. Therefore several neuropathologies are associated with defects in proteins located at the spines. The present work is focused on the spine actin cytoskeleton attending to its structure and function mainly in glutamatergic neurons. It addresses the study of the structural plasticity of dendritic spines associated with long-term potentiation (LTP) and the mechanisms that underlie learning and memory formation. We have integrated the current knowledge on synaptic proteins to relate this plethora of molecules with actin and actin-binding proteins. We further included recent findings that outline key uncharacterized proteins that would be useful to unveil the real ultrastructure and function of dendritic spines. Furthermore, this review is directed to understand how such spine diversity and interplay contributes to the regulation of spine morphogenesis and dynamics. It highlights their physiological relevance in the brain function, as well as it provides insights for pathological processes affecting dramatically dendritic spines, such as Alzheimer's disease.
Molecular biology of the cell, 2015
The morphology of neuronal dendritic spines is a critical indicator of synaptic function. It is regulated by several factors, including the intracellular actin/myosin cytoskeleton and trans-cellular N-cadherin adhesions. To examine the mechanical relationship between these molecular components, we performed quantitative live imaging experiments in primary hippocampal neurons. We found that actin turnover and structural motility were lower in dendritic spines than in immature filopodia, and increased upon expression of a non-adhesive N-cadherin mutant, resulting in an inverse relationship between spine motility and actin enrichment. Furthermore, the pharmacological stimulation of myosin II induced the rearward motion of actin structures in spines, revealing that myosin II exerts tension on the actin network. Strikingly, the formation of stable spine-like structures enriched in actin was induced at contacts between dendritic filopodia and N-cadherin coated beads or micropatterns. Fina...
Structural Plasticity of Dendritic Spines
Dendritic spines are small mushroom-like protrusions arising from neurons where most excitatory synapses reside. Their peculiar shape suggests that spines can serve as an autonomous postsynaptic compartment that isolates chemical and electrical signaling. How neuronal activity modifies the morphology of the spine and how these modifications affect synaptic transmission and plasticity are intriguing issues. Indeed, the induction of long-term potentiation (LTP) or depression (LTD) is associated with the enlargement or shrinkage of the spine, respectively. This structural plasticity is mainly controlled by actin filaments, the principal cytoskeletal component of the spine. Here we review the pioneering microscopic studies examining the structural plasticity of spines and propose how changes in actin treadmilling might regulate spine morphology.