scholarly journals Endophilin A1 promotes Actin Polymerization in response to Ca2+/calmodulin to Initiate Structural Plasticity of Dendritic Spines

2020 ◽  
Author(s):  
Yanrui Yang ◽  
Jiang Chen ◽  
Xue Chen ◽  
Di Li ◽  
Jianfeng He ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Actin Polymerization ◽  
Morphological Changes ◽  
Structural Plasticity ◽  
Long Term Potentiation ◽  
Membrane Dynamics ◽  
Long Term Memory ◽  
Induction Phase ◽  
Term Potentiation

AbstractDendritic spines of excitatory neurons undergo activity-dependent structural and functional plasticity, which are cellular correlates of learning and memory. However, mechanisms underlying the rapid morphological changes immediately after NMDAR-mediated Ca2+ influx into spines remain poorly understood. Here we report that endophilin A1, a neuronal N-BAR protein, orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in the induction phase of long-term potentiation (LTP). Upon LTP induction, Ca2+/calmodulin enhances its binding to both membrane and p140Cap, a cytoskeleton regulator. As a result, endophilin A1 rapidly associates with the relaxed plasma membrane and promotes actin polymerization, leading to acute expansion of spine head. Moreover, not only the p140Cap-binding, but also calmodulin- and membrane-binding capacities of endophilin A1 are required for LTP and long-term memory. Thus, endophilin A1 functions as calmodulin effector to drive spine enlargement in response to Ca2+ influx in the initial phase of structural plasticity.

scholarly journals Endophilin A1 drives acute structural plasticity of dendritic spines in response to Ca2+/calmodulin

2021 ◽  
Vol 220 (6) ◽  
Author(s):  
Yanrui Yang ◽  
Jiang Chen ◽  
Xue Chen ◽  
Di Li ◽  
Jianfeng He ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Dendritic Spines ◽  
Actin Polymerization ◽  
Structural Plasticity ◽  
Long Term Potentiation ◽  
Membrane Dynamics ◽  
Long Term Memory ◽  
Term Memory ◽  
Term Potentiation

Induction of long-term potentiation (LTP) in excitatory neurons triggers a large transient increase in the volume of dendritic spines followed by decays to sustained size expansion, a process termed structural LTP (sLTP) that contributes to the cellular basis of learning and memory. Although mechanisms regulating the early and sustained phases of sLTP have been studied intensively, how the acute spine enlargement immediately after LTP stimulation is achieved remains elusive. Here, we report that endophilin A1 orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in NMDAR-mediated LTP. Upon LTP induction, Ca2+/calmodulin enhances binding of endophilin A1 to both membrane and p140Cap, a cytoskeletal regulator. Consequently, endophilin A1 rapidly localizes to the plasma membrane and recruits p140Cap to promote local actin polymerization, leading to spine head expansion. Moreover, its molecular functions in activity-induced rapid spine growth are required for LTP and long-term memory. Thus, endophilin A1 serves as a calmodulin effector to drive acute structural plasticity necessary for learning and memory.

scholarly journals Long-Term Potentiation in Isolated Dendritic Spines

PLoS ONE ◽  
2009 ◽  
Vol 4 (6) ◽  
pp. e6021 ◽  
Author(s):  
Amadou T. Corera ◽  
Guy Doucet ◽  
Edward A. Fon
Keyword(s):  
Dendritic Spines ◽  
Long Term Potentiation ◽  
Term Potentiation

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

scholarly journals Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

2019 ◽  
Vol 400 (9) ◽  
pp. 1129-1139 ◽  
Author(s):  
Iryna Hlushchenko ◽  
Pirta Hotulainen
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Signal Molecule ◽  
Brain Functions ◽  
Dendritic Shaft ◽  
Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

scholarly journals Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Silvia Pelucchi ◽  
Lina Vandermeulen ◽  
Lara Pizzamiglio ◽  
Bahar Aksan ◽  
Jing Yan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Actin Cytoskeleton ◽  
Structural Plasticity ◽  
Long Term Potentiation ◽  
Brain Diseases ◽  
Biological Trait ◽  
Term Potentiation ◽  
Cytoskeleton Dynamics

Abstract Regulation of actin cytoskeleton dynamics in dendritic spines is crucial for learning and memory formation. Hence, defects in the actin cytoskeleton pathways are a biological trait of several brain diseases, including Alzheimer's disease. Here, we describe a novel synaptic mechanism governed by the cyclase-associated protein 2, which is required for structural plasticity phenomena and completely disrupted in Alzheimer's disease. We report that the formation of cyclase-associated protein 2 dimers through its Cys32 is important for cyclase-associated protein 2 binding to cofilin and for actin turnover. The Cys32-dependent cyclase-associated protein 2 homodimerization and association to cofilin are triggered by long-term potentiation and are required for long-term potentiation-induced cofilin translocation into spines, spine remodelling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer's disease patients and APP/PS1 mice, where cyclase-associated protein 2 is down-regulated and cyclase-associated protein 2 dimer synaptic levels are reduced. Notably, cyclase-associated protein 2 levels in the cerebrospinal fluid are significantly increased in Alzheimer's disease patients but not in subjects affected by frontotemporal dementia. In Alzheimer's disease hippocampi, cofilin association to cyclase-associated protein 2 dimer/monomer is altered and cofilin is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in Alzheimer's disease.

scholarly journals Structural basis of long-term potentiation in single dendritic spines

Nature ◽  
2004 ◽  
Vol 429 (6993) ◽  
pp. 761-766 ◽  
Author(s):  
Masanori Matsuzaki ◽  
Naoki Honkura ◽  
Graham C. R. Ellis-Davies ◽  
Haruo Kasai
Keyword(s):  
Dendritic Spines ◽  
Long Term Potentiation ◽  
Structural Basis ◽  
Term Potentiation

scholarly journals Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice

2016 ◽  
Vol 311 (1) ◽  
pp. R166-R178 ◽  
Author(s):  
Bruce C. Kennedy ◽  
Jiva G. Dimova ◽  
Srikanth Dakoji ◽  
Li-Lian Yuan ◽  
Jonathan C. Gewirtz ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Pathway Analysis ◽  
Transmembrane Protein ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Molecular Networks ◽  
Long Term Memory ◽  
Term Memory ◽  
Term Potentiation

The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-d-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry.

scholarly journals Large and Small Dendritic Spines Serve Different Interacting Functions in Hippocampal Synaptic Plasticity and Homeostasis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Joshua J. W. Paulin ◽  
Peter Haslehurst ◽  
Alexander D. Fellows ◽  
Wenfei Liu ◽  
Joshua D. Jackson ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Fluorescent Protein ◽  
Long Term Potentiation ◽  
Functional Differentiation ◽  
Strong Stimulus ◽  
Term Potentiation ◽  
Original Size ◽  
Green Fluorescent ◽  
Homeostatic Response

The laying down of memory requires strong stimulation resulting in specific changes in synaptic strength and corresponding changes in size of dendritic spines. Strong stimuli can also be pathological, causing a homeostatic response, depressing and shrinking the synapse to prevent damage from too much Ca2+influx. But do all types of dendritic spines serve both of these apparently opposite functions? Using confocal microscopy in organotypic slices from mice expressing green fluorescent protein in hippocampal neurones, the size of individual spines along sections of dendrite has been tracked in response to application of tetraethylammonium. This strong stimulus would be expected to cause both a protective homeostatic response and long-term potentiation. We report separation of these functions, with spines of different sizes reacting differently to the same strong stimulus. The immediate shrinkage of large spines suggests a homeostatic protective response during the period of potential danger. In CA1, long-lasting growth of small spines subsequently occurs consolidating long-term potentiation but only after the large spines return to their original size. In contrast, small spines do not change in dentate gyrus where potentiation does not occur. The separation in time of these changes allows clear functional differentiation of spines of different sizes.

scholarly journals Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation

2008 ◽  
Vol 294 (2) ◽  
pp. C503-C515 ◽  
Author(s):  
Paul Smolen ◽  
Douglas A. Baxter ◽  
John H. Byrne
Keyword(s):  
Map Kinase ◽  
Dendritic Spine ◽  
Mapk Pathway ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Stable States ◽  
Mapk Activity ◽  
Stochastic Fluctuations ◽  
Term Potentiation

Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (Markevich NI, Hoek JB, Kholodenko BN. J Cell Biol 164: 353–359, 2004) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability was present only within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive-feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations and to parameter variations. Bistability was robust for molecule numbers plausible for a dendritic spine volume. The upper state of MAPK activity was resistant to inhibition of MEK activation for >1 h, which suggests that inhibitor experiments have not sufficed to rule out a role for persistent MAPK activity in the maintenance of long-term potentiation (LTP). These simulations suggest that persistent MAPK activity and consequent upregulation of translation may contribute to LTP maintenance and to long-term memory. Experiments using a fluorescent MAPK substrate may further test this hypothesis.

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