Actin remodeling of neurons
Encyclopedia
Actin remodeling is a biochemical
process in cells
. In the actin remodeling
of neurons, the protein
actin is part of the process to change the shape and structure of dendritic spine
s. G-actin is the monomer
form of actin
, and is uniformly distributed throughout the axon
and the dendrite
. F-actin is the polymer
form of actin, and its presence in dendritic spines is associated with their change in shape and structure. Actin plays a role in the formation of new spines as well as stabilizing spine volume increase. The changes that actin brings about leads to the formation of new synapses as well as increased cell communication.
Actin remodeling consists of the dynamic changes in actin polymerization
that underlie the morphological
changes at the neural synapse
. Actin is only able to cause all of the changes that promote long-term potentiation
(LTP) through its formation from G-actin into F-actin. When F-actin is unable to form, long-term depression
(LTD) is induced, which promotes opposite results. Stimulation of the neuron that promotes LTP causes larger spine volume, increased cell communication, and a greater ratio of F-actin to G-actin. In the LTD environment, spine volume is decreased, cell communication is decreased, and there is a far greater ratio of G-actin to F-actin.
F-actin can be found in the presynaptic bouton surrounding synaptic vesicle clusters and acting as scaffolding. Additionally, actin is present at the active zone and plays a role in moving vesicles to the active zone for exocytosis into the synapse. The active zone is the portion of the presynaptic membrane opposite the postsynaptic density across the synaptic cleft. It is the site of synaptic vesicle docking and neurotransmitter release. Postsynaptically, F-actin can be found in the postsynaptic density zone (PSDZ) and throughout the spine head and neck. G-actin is uniformly distributed throughout the axon and the dendrite.
The balance of F and G-actin is in a constant state of flux, and this can be attributed to actin treadmilling. Actin treadmilling is the process of turnover of actin filaments where F-actin is rapidly assembled and disassembled. G-actin subunits preferentially add to the barbed end of the F-actin polymer and older units are removed from the pointed end. The concentration of free G-actin monomers decreases until it reaches a critical concentration where the rate of assembly to disassembly or the F to G-actin ratio reaches a steady state.
. This protein allows for many changes both presynaptically and postsynaptically.
In the presynaptic region, actin allows for the formation of new axonal branches that result in new boutons. It also facilitates vesicle recruitment to the bouton.
Postsynaptically, actin filaments traffic AMPA receptors to the PSDZ, while also providing scaffolding for plasticity products such as CAMKII. F-actin could serve as a synaptic tag because the scaffolding space for plasticity products is increased during LTP actin polymerization. Furthermore, the actin cytoskeleton in the neck of the spine compartmentalizes the LTP induced response to the innervated dendritic spine, which leads to the specificity of LTP. Actin plays a role in the formation of new spines as well as stabilized spine volume increase. All of these changes that actin brings about leads to the formation of new synapses as well as increased cell communication.
LTP inducing high frequency stimulation leads to NMDA receptor activation and calcium influx. Rho GTPases are then activated to polymerize G-actin to F-actin through the activity of actin binding proteins. An increase in the F-actin/G-actin ratio is observed 40 seconds after the LTP inducing stimulus. The increase in polymerized F-actin is due to the recruitment of G-actin monomers and the translation of actin mRNA in the dendrite. The stimulus induced change persists for approximately 5 weeks.
Actin is only able to cause all of the changes that promote LTP through its formation into F-actin. When F-actin is unable to form, LTD
is induced, which promotes opposite results.
This figure demonstrates the morphological effects on the dendrites in LTP and LTD environments. In LTP we can see the larger spine volume as well as a greater ratio of F-actin to G-actin. This demonstrates the role of actin in LTP as well as the increased communication LTP creates. In the LTD environment, spine volume is decreased and there is a far greater ratio of G-actin to F-actin, demonstrating the importance of the F-actin to G-actin ratios in both LTP and LTD.
LIMK1, an actin binding protein, phosphorylates ADF/cofilin, allowing for the formation of F-actin. LIMK1 knockout neurons are unable to form a cytoskeletal matrix within the dendritic spine, which has interesting implications for learning. One of the primary functions of actin is to compartmentalize a neuron’s response to stimulation – that is, to keep molecules essential for LTP within the stimulated spine. Upon low frequency stimulation of knockout cells, these molecules are likely to diffuse out of the cell before a concentration significant enough to produce LTP builds up. Upon high frequency stimulation, however, there is an overabundance of these essential molecules, which are present in high enough concentrations to produce LTP not only at the stimulated spine but at the adjacent spines they diffuse into as a result of a lack of compartmentalization. The result is an overall increase in potentiation.
In humans, many heritable disorders characterized by mental retardation are linked to mutations in genes important to the actin polymerization pathway. Williams syndrome, fragile X, fetal alcohol syndrome, and Patau syndrome have all been linked to these genes. Neurons from people affected by these disorders show minimal dendritic arborization and undeveloped spine structure, similar to neurons in animal models of molecular defects in actin polymerization.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
process in cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. In the actin remodeling
Actin remodeling
Actin remodeling is a biochemical process in cells. In actin remodeling, there is a cycle of actin monomers being polymerized, affecting the cell membrane, and being broken down into monomers again...
of neurons, the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
actin is part of the process to change the shape and structure of dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
s. G-actin is the monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
form of actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
, and is uniformly distributed throughout the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
and the dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
. F-actin is the polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
form of actin, and its presence in dendritic spines is associated with their change in shape and structure. Actin plays a role in the formation of new spines as well as stabilizing spine volume increase. The changes that actin brings about leads to the formation of new synapses as well as increased cell communication.
Actin remodeling consists of the dynamic changes in actin polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
that underlie the morphological
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
changes at the neural synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. Actin is only able to cause all of the changes that promote long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP) through its formation from G-actin into F-actin. When F-actin is unable to form, long-term depression
Long-term depression
Long-term depression , in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress...
(LTD) is induced, which promotes opposite results. Stimulation of the neuron that promotes LTP causes larger spine volume, increased cell communication, and a greater ratio of F-actin to G-actin. In the LTD environment, spine volume is decreased, cell communication is decreased, and there is a far greater ratio of G-actin to F-actin.
Structural overview of actin
Actin exists in two states in the axonal and dendritic processes: globular or G-actin and filament/filamentous or F-actin. G-actin are the monomer building blocks that assemble via weak noncovalent interactions to form F-actin. F-actin is a two-stranded asymmetrical helical polymer. The asymmetrical quality of F-actin allows for different binding specificities at each end. One end shows an indentation and is referred to as the barbed end while the other resembles an arrow head and is referred to as the pointed end.F-actin can be found in the presynaptic bouton surrounding synaptic vesicle clusters and acting as scaffolding. Additionally, actin is present at the active zone and plays a role in moving vesicles to the active zone for exocytosis into the synapse. The active zone is the portion of the presynaptic membrane opposite the postsynaptic density across the synaptic cleft. It is the site of synaptic vesicle docking and neurotransmitter release. Postsynaptically, F-actin can be found in the postsynaptic density zone (PSDZ) and throughout the spine head and neck. G-actin is uniformly distributed throughout the axon and the dendrite.
The balance of F and G-actin is in a constant state of flux, and this can be attributed to actin treadmilling. Actin treadmilling is the process of turnover of actin filaments where F-actin is rapidly assembled and disassembled. G-actin subunits preferentially add to the barbed end of the F-actin polymer and older units are removed from the pointed end. The concentration of free G-actin monomers decreases until it reaches a critical concentration where the rate of assembly to disassembly or the F to G-actin ratio reaches a steady state.
Role in short-term synaptic communication
Non-LTP inducing stimulus causes alterations in spine morphology due to changes in actin polymerization. Presynaptically, axonal boutons undergo submicron displacements that indent the dendritic spines. Postsynaptically, innervation causes dendritic spines to remodel by as much as 30% over a period of seconds. The spines show a lateral expansion that envelops the presynaptic axonal indentation. The changes due to non-LTP inducing stimuli dissipate after 5 minutes.Role in LTP and LTD
Actin is necessary for the induction of LTPLong-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
. This protein allows for many changes both presynaptically and postsynaptically.
In the presynaptic region, actin allows for the formation of new axonal branches that result in new boutons. It also facilitates vesicle recruitment to the bouton.
Postsynaptically, actin filaments traffic AMPA receptors to the PSDZ, while also providing scaffolding for plasticity products such as CAMKII. F-actin could serve as a synaptic tag because the scaffolding space for plasticity products is increased during LTP actin polymerization. Furthermore, the actin cytoskeleton in the neck of the spine compartmentalizes the LTP induced response to the innervated dendritic spine, which leads to the specificity of LTP. Actin plays a role in the formation of new spines as well as stabilized spine volume increase. All of these changes that actin brings about leads to the formation of new synapses as well as increased cell communication.
LTP inducing high frequency stimulation leads to NMDA receptor activation and calcium influx. Rho GTPases are then activated to polymerize G-actin to F-actin through the activity of actin binding proteins. An increase in the F-actin/G-actin ratio is observed 40 seconds after the LTP inducing stimulus. The increase in polymerized F-actin is due to the recruitment of G-actin monomers and the translation of actin mRNA in the dendrite. The stimulus induced change persists for approximately 5 weeks.
Actin is only able to cause all of the changes that promote LTP through its formation into F-actin. When F-actin is unable to form, LTD
Long-term depression
Long-term depression , in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress...
is induced, which promotes opposite results.
This figure demonstrates the morphological effects on the dendrites in LTP and LTD environments. In LTP we can see the larger spine volume as well as a greater ratio of F-actin to G-actin. This demonstrates the role of actin in LTP as well as the increased communication LTP creates. In the LTD environment, spine volume is decreased and there is a far greater ratio of G-actin to F-actin, demonstrating the importance of the F-actin to G-actin ratios in both LTP and LTD.
Actin binding proteins in LTP and LTD
Actin binding proteins prove significant in actin remodeling, as the LIMK1/ADF/Cofilin Pathway facilitates the development of F-actin. Actin Depolymerizing Factor, or ADF, normally disassembles actin and does not allow for the induction of LTP. However, synaptic activity allows for the activation of LIMK1, a protein that phosphorylates the ADF/Cofilin complex at its phosphorylation site, Ser3, which inactivates the complex, allowing for the formation of F-actin. If this pathway is disrupted, then G-actin is unable to polymerize and LTP is inhibited. One particular actin binding protein that plays a major role in this pathway disruption is Gelsolin. This protein caps the barbed end of F-actin, thus blocking G-actin subunits to bind to the F-actin and allow for actin treadmilling. Activation of Gelsolin not only blocks LTP, but induces LTD. In LTD, the F to G-actin ratio is shifted towards G-actin and leads to a decrease in spine volume, as well as occasional disappearance of spines altogether.Implications for learning and memory
Being associated with long term structural changes at the synapse and LTP, it is no surprise that actin dynamics influence learning and memory. Experiments have shown that drugs like cytochatasin C and latrunculin A that inhibit the assembly of G-actin into F-actin disrupt both the acquisition and extinction of fear responses in mice. Disruption of actin dynamics can also affect visuospatial learning.LIMK1, an actin binding protein, phosphorylates ADF/cofilin, allowing for the formation of F-actin. LIMK1 knockout neurons are unable to form a cytoskeletal matrix within the dendritic spine, which has interesting implications for learning. One of the primary functions of actin is to compartmentalize a neuron’s response to stimulation – that is, to keep molecules essential for LTP within the stimulated spine. Upon low frequency stimulation of knockout cells, these molecules are likely to diffuse out of the cell before a concentration significant enough to produce LTP builds up. Upon high frequency stimulation, however, there is an overabundance of these essential molecules, which are present in high enough concentrations to produce LTP not only at the stimulated spine but at the adjacent spines they diffuse into as a result of a lack of compartmentalization. The result is an overall increase in potentiation.
In humans, many heritable disorders characterized by mental retardation are linked to mutations in genes important to the actin polymerization pathway. Williams syndrome, fragile X, fetal alcohol syndrome, and Patau syndrome have all been linked to these genes. Neurons from people affected by these disorders show minimal dendritic arborization and undeveloped spine structure, similar to neurons in animal models of molecular defects in actin polymerization.