The actin cytoskeleton and synaptic plasticity. (original) (raw)
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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
The Formation of Synapses in the Central Nervous System
Molecular Neurobiology, 2002
Synaptic contacts are asymmetric and highly specialized contact zones established between the transmitting pole (the axon) of a presynaptic neuron and the receptive pole (either the dendrites or the soma) of the target nerve cells. Synaptogenesis, the final step in neuronal development, is the result of cellular events related to neurite elongation, the establishment of polarity, axon guidance, and target recognition (1-3). The formation of these specific connections underlies normal functioning of the nervous system, and, therefore, has been the subject of numerous studies over the past three decades. Most of these studies have used the neuromuscular junction as a model system, both for its simplicity and its accessibility to experimental manipulations. A growing body of evidence indicates that, at the neuromuscular junction, the initial contact of an axonal growth cone with a muscle cell initiates a series
Analysis of Cell Adhesion Molecules in Synapse Formation and Synaptic Transmission
2015
for his constant support and inspiration. Last but not least, I like to remember supports from my parents, sisters and brother throughout my career. Thanks to my teachers and friends. Elucidation of brain function is important for our healthy survival and understanding diseases, I like to thank all those who are guiding me in specific direction of brain research.
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...