scholarly journals Control of Dendritic Spine Morphological and Functional Plasticity by Small GTPases

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Kevin M. Woolfrey ◽  
Deepak P. Srivastava
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neuronal Development ◽  
Structural Plasticity ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Abnormal Development ◽  
Actin Dynamics ◽  
Excitatory Synapses ◽  
Spine Structure

Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity, and behaviour. Abnormal development or regulation of excitatory synapses has also been strongly implicated in many neurodevelopmental, psychiatric, and neurodegenerative disorders. In the mammalian forebrain, the majority of excitatory synapses are located on dendritic spines, specialized dendritic protrusions that are enriched in actin. Research over recent years has begun to unravel the complexities involved in the regulation of dendritic spine structure. The small GTPase family of proteins have emerged as key regulators of structural plasticity, linking extracellular signals with the modulation of dendritic spines, which potentially underlies their ability to influence cognition. Here we review a number of studies that examine how small GTPases are activated and regulated in neurons and furthermore how they can impact actin dynamics, and thus dendritic spine morphology. Elucidating this signalling process is critical for furthering our understanding of the basic mechanisms by which information is encoded in neural circuits but may also provide insight into novel targets for the development of effective therapies to treat cognitive dysfunction seen in a range of neurological disorders.

scholarly journals Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis

2009 ◽  
Vol 185 (2) ◽  
pp. 323-339 ◽  
Author(s):  
Pirta Hotulainen ◽  
Olaya Llano ◽  
Sergei Smirnov ◽  
Kimmo Tanhuanpää ◽  
Jan Faix ◽  
...  
Keyword(s):  
Actin Filament ◽  
Dendritic Spines ◽  
Actin Polymerization ◽  
Morphological Changes ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Excitatory Synapses ◽  
Mature Brain ◽  
Key Steps ◽  
Spine Morphogenesis

Dendritic spines are small protrusions along dendrites where the postsynaptic components of most excitatory synapses reside in the mature brain. Morphological changes in these actin-rich structures are associated with learning and memory formation. Despite the pivotal role of the actin cytoskeleton in spine morphogenesis, little is known about the mechanisms regulating actin filament polymerization and depolymerization in dendritic spines. We show that the filopodia-like precursors of dendritic spines elongate through actin polymerization at both the filopodia tip and root. The small GTPase Rif and its effector mDia2 formin play a central role in regulating actin dynamics during filopodia elongation. Actin filament nucleation through the Arp2/3 complex subsequently promotes spine head expansion, and ADF/cofilin-induced actin filament disassembly is required to maintain proper spine length and morphology. Finally, we show that perturbation of these key steps in actin dynamics results in altered synaptic transmission.

scholarly journals BDNF signaling during the lifetime of dendritic spines

2020 ◽  
Vol 382 (1) ◽  
pp. 185-199 ◽  
Author(s):  
Marta Zagrebelsky ◽  
Charlotte Tacke ◽  
Martin Korte
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Conclusive Evidence ◽  
Excitatory Synapses ◽  
Neuronal Homeostasis ◽  
Bdnf Signaling ◽  
Spine Number

Abstract Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

Development and Regulation of Dendritic Spine Synapses

Physiology ◽  
2006 ◽  
Vol 21 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Barbara Calabrese ◽  
Margaret S. Wilson ◽  
Shelley Halpain
Keyword(s):  
Synaptic Transmission ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Excitatory Synapses ◽  
Dense Array ◽  
Complex Dynamic ◽  
Neuronal Dendrites ◽  
Spine Abnormalities ◽  
Dynamic Structures ◽  
The Brain

Dendritic spines are small protrusions from neuronal dendrites that form the postsynaptic component of most excitatory synapses in the brain. They play critical roles in synaptic transmission and plasticity. Recent advances in imaging and molecular technologies reveal that spines are complex, dynamic structures that contain a dense array of cytoskeletal, transmembrane, and scaffolding molecules. Several neurological and psychiatric disorders exhibit dendritic spine abnormalities.

scholarly journals EPAC2 is required for corticotropin-releasing hormone-mediated spine loss

2019 ◽  
Author(s):  
Zhong Xie ◽  
Peter Penzes ◽  
Deepak P. Srivastava
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Cortical Neurons ◽  
Acute Stress ◽  
Critical Role ◽  
Small Gtpase ◽  
Corticotropin Releasing Hormone ◽  
Rapid Loss ◽  
Primary Cortical Neurons ◽  
Releasing Hormone

AbstractCorticotropin-releasing hormone (CRH) is produced in response to stress. This hormone plays a key role in mediating neuroendocrine, behavioral, and autonomic responses to stress. The CRH receptor 1 (CRHR1) is expressed in multiple brain regions including the cortex and hippocampus. Previous studies have shown that activation of CRHR1 by CRH results in the rapid loss of dendritic spines. Exchange protein directly activated by cAMP (EPAC2, also known as RapGEF4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rap, has been linked with CRHR1 signaling. EPAC2 plays a critical role in regulating dendritic spine morphology and number in response to several extracellular signals. But whether EPAC2 links CRHR1 with dendritic spine remodeling is unknown. Here we show that CRHR1 is highly enriched in the dendritic spines of primary cortical neurons. Furthermore, we find that EPAC2 and CRHR1 co-localize in cortical neurons. Critically, short hairpin RNA-mediated knockdown of Epac2 abolished CRH-mediated spine loss in primary cortical neurons. Taken together, our data indicate that EPAC2 is required for the rapid loss of dendritic spines induced by CRH. These findings identify a novel pathway by which acute exposure to CRH may regulate synaptic structure and ultimately responses to acute stress.

scholarly journals Dendritic spine geometry can localize GTPase signaling in neurons

2015 ◽  
Vol 26 (22) ◽  
pp. 4171-4181 ◽  
Author(s):  
Samuel A. Ramirez ◽  
Sridhar Raghavachari ◽  
Daniel J. Lew
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Primary Cilia ◽  
Reaction Diffusion ◽  
Reaction Diffusion Equations ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Sustained Activation

Dendritic spines are the postsynaptic terminals of most excitatory synapses in the mammalian brain. Learning and memory are associated with long-lasting structural remodeling of dendritic spines through an actin-mediated process regulated by the Rho-family GTPases RhoA, Rac, and Cdc42. These GTPases undergo sustained activation after synaptic stimulation, but whereas Rho activity can spread from the stimulated spine, Cdc42 activity remains localized to the stimulated spine. Because Cdc42 itself diffuses rapidly in and out of the spine, the basis for the retention of Cdc42 activity in the stimulated spine long after synaptic stimulation has ceased is unclear. Here we model the spread of Cdc42 activation at dendritic spines by means of reaction-diffusion equations solved on spine-like geometries. Excitable behavior arising from positive feedback in Cdc42 activation leads to spreading waves of Cdc42 activity. However, because of the very narrow neck of the dendritic spine, wave propagation is halted through a phenomenon we term geometrical wave-pinning. We show that this can account for the localization of Cdc42 activity in the stimulated spine, and, of interest, retention is enhanced by high diffusivity of Cdc42. Our findings are broadly applicable to other instances of signaling in extreme geometries, including filopodia and primary cilia.

scholarly journals eEF1A2 controls local translation and actin dynamics in structural synaptic plasticity

2020 ◽  
Author(s):  
Mònica B. Mendoza ◽  
Sara Gutierrez ◽  
Raúl Ortiz ◽  
David F. Moreno ◽  
Maria Dermit ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Metabotropic Glutamate Receptor ◽  
Elongation Factor ◽  
Structural Plasticity ◽  
Actin Dynamics ◽  
Dependent Manner ◽  
Local Translation ◽  
Translation Elongation Factor ◽  
Translation Elongation

AbstractSynaptic plasticity involves structural modifications in dendritic spines. Increasing evidence suggests that structural plasticity is modulated by local protein synthesis and actin remodeling in a synapsis-specific manner. However, the precise molecular mechanisms connecting synaptic stimulation to these processes in dendritic spines are still unclear. In the present study, we demonstrate that the configuration of phosphorylation sites in eEF1A2, an essential translation elongation factor in neurons, is a key modulator of structural plasticity in dendritic spines. A mutant that cannot be phosphorylated stimulates translation but reduces actin dynamics and spine density. By contrast, the phosphomimetic variant loosens its association with F-actin and becomes inactive as a translation elongation factor. Metabotropic glutamate receptor signaling triggers a transient dissociation of eEF1A2 from its GEF protein in dendritic spines, in a phospho-dependent manner. We propose that eEF1A2 establishes a crosstalk mechanism that coordinates local translation and actin dynamics during spine remodeling.

scholarly journals Mouse A6/Twinfilin Is an Actin Monomer-Binding Protein That Localizes to the Regions of Rapid Actin Dynamics

2000 ◽  
Vol 20 (5) ◽  
pp. 1772-1783 ◽  
Author(s):  
Maria Vartiainen ◽  
Pauli J. Ojala ◽  
Petri Auvinen ◽  
Johan Peränen ◽  
Pekka Lappalainen
Keyword(s):  
Tyrosine Kinase ◽  
Binding Protein ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Cell Cortex ◽  
Actin Monomer

ABSTRACT In our database searches, we have identified mammalian homologues of yeast actin-binding protein, twinfilin. Previous studies suggested that these mammalian proteins were tyrosine kinases, and therefore they were named A6 protein tyrosine kinase. In contrast to these earlier studies, we did not find any tyrosine kinase activity in our recombinant protein. However, biochemical analysis showed that mouse A6/twinfilin forms a complex with actin monomer and prevents actin filament assembly in vitro. A6/twinfilin mRNA is expressed in most adult tissues but not in skeletal muscle and spleen. In mouse cells, A6/twinfilin protein is concentrated to the areas at the cell cortex which overlap with G-actin-rich actin structures. A6/twinfilin also colocalizes with the activated forms of small GTPases Rac1 and Cdc42 to membrane ruffles and to cell-cell contacts, respectively. Furthermore, expression of the activated Rac1(V12) in NIH 3T3 cells leads to an increased A6/twinfilin localization to nucleus and cell cortex, whereas a dominant negative form of Rac1(V12,N17) induces A6/twinfilin localization to cytoplasm. Taken together, these studies show that mouse A6/twinfilin is an actin monomer-binding protein whose localization to cortical G-actin-rich structures may be regulated by the small GTPase Rac1.

scholarly journals Rac1 is a downstream effector of PKCα in structural synaptic plasticity

2019 ◽  
Author(s):  
Xun Tu ◽  
Ryohei Yasuda ◽  
Lesley A Colgan
Keyword(s):  
Dendritic Spines ◽  
Structural Plasticity ◽  
Small Gtpases ◽  
Functional Plasticity ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Downstream Effector ◽  
Kinase C ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinase

AbstractStructural and functional plasticity of dendritic spines is the basis of animal learning. The calcium-dependent protein kinase C isoform, PKCα, has been suggested to be critical for this actin-dependent plasticity. However, mechanisms linking PKCα and structural plasticity of spines are unknown. Here, we examine the spatiotemporal activation of actin regulators, including small GTPases Rac1, Cdc42 and Ras, in the presence or absence of PKCα during single-spine structural plasticity. Removal of PKCα expression in the postsynapse attenuated Rac1 activation during structural plasticity without affecting Ras or Cdc42 activity. Moreover, disruption of a PDZ binding domain within PKCα led to impaired Rac1 activation and deficits in structural spine remodeling. These results demonstrate that PKCα positively regulates the activation of Rac1 during structural plasticity.

scholarly journals Neuronal actin dynamics, spine density and neuronal dendritic complexity are regulated by CAP2

2015 ◽  
Author(s):  
Atul Kumar ◽  
Lars Paeger ◽  
Kosmas Kosmas ◽  
Peter Kloppenburg ◽  
Angelika Noegel ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Neuronal Development ◽  
Actin Dynamics ◽  
Spine Density ◽  
Delayed Wound Healing ◽  
Actin Remodeling ◽  
Cardiovascular Defects ◽  
Dendritic Complexity

Actin remodeling is indispensable for dendritic spine development, morphology and density which signify learning, memory and motor skills. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2gt/gt mice. Dendritic spine density and neuronal dendritic length were altered in Cap2gt/gt. This was accompanied by increased F-actin content and F-actin accumulation in cultured Cap2gt/gt neurons. In membrane depolarization assays, Cap2gt/gt synaptosomes exhibit an impaired F/G actin ratio, indicating altered actin dynamics. We show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and is cofilin ser3 phosphorylation dependent. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics.

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