Synaptic stabilization

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Synaptic stabilization by cell adhesion molecules Synaptic stabilization by cell adhesion molecules.svg
Synaptic stabilization by cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. [1] [2] In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory. [3]

Contents

Types of CAMs

SynCAMs

Synaptic cell adhesion molecules (CAMs) play a crucial role in axon pathfinding and synaptic establishment between neurons during neurodevelopment and are integral members in many synaptic processes including the correct alignment of pre- and post-synaptic signal transduction pathways, vesicular recycling in regards to endocytosis and exocytosis, integration of postsynaptic receptors and anchoring to the cytoskeleton to ensure stability of synaptic components [4]

SynCAM’s (also known as Cadm or nectin-like molecules) are a specific type of synaptic CAM found in vertebrates that promotes growth and stabilization of excitatory (not inhibitory) synapses. SynCAM’s are localized primarily in the brain at both pre- and postsynaptic sites and their structures consist of intracellular FERM and PDZ binding domains, a single transmembrane domain, and three extracellular Ig-domains. During neurodevelopment, SynCAMs such as SynCAM1 act as “contact sensors” of axonal growth cones accumulating rapidly when axo-dendritic connections are made and helping to form a stable adhesion complex. [5]

synCAM1 along with neuroligin are the two CAM’s known to be sufficient to initiate the formation of presynaptic terminals, as addition of synCAM1 to media of co-cultured neuronal and non-neuronal cells lead to the establishment of presynaptic terminals. Homophillic binding of two synCAM1 molecules on the filopodia of axonal growth cone and dendritic spine allow for initial contact between pre- and postsynaptic cell to be made. [6]

synCAMs belong to the Ig superfamily of proteins. The cytosolic PDZ domains of synCAMs imbedded in the post-synaptic membrane interact with post-synaptic scaffold protein PSD-95 which helps anchor the complex to the underlying cytoskeleton. [7]

Cadherin-catenin

Temporal and spatial distribution of N-cadherin complexes in the developing and mature synapse Localization of cadherin-catenin.jpg
Temporal and spatial distribution of N-cadherin complexes in the developing and mature synapse

Cadherins are calcium- dependent, homophilic cell adhesion molecules that form complexes with cytosolic partners known as catenins. [8] Components of this complex bind to a number of different scaffolding proteins, phosphotases, kinases, and receptors. [9] Classical cadherins have five extracellular repeating structures which bind calcium, a single transmembrane domain, and an intracellular tail with a distal cytosolic domain that binds a catenin partner. [9] [10] Recent work has implicated the cadherin-catenin complex in a number of different central nervous system processes such as synaptic stabilization and plasticity. [8] [9] [10]

Many cadherins in the central nervous system exhibit distinct spatial and temporal expression patterns. [9] For example, N-cadherin is widely expressed at the developing synapse and later remains near the mature active zone implicating that this complex may be well-suited to provide a link between structural changes and synaptic stability. [9] In fact, local synaptic activity changes impact the expression of the cadherin-catenin complexes. [9] An increase in activity at a particular spine leads to the dimerization of N-cadherin which is then cleaved leading the repression of CBP/CREB transcription. [9] This repression has many developmental and plasticity related implications.

In the case of dendritic spine formation and pruning, a competition hypothesis has been proposed and corroborated. [11] [12] This hypothesis suggests that relative levels of cadherin-catenin complexes, which are distributed amongst spines in a local area in an activity-dependent manner, determines the fate of individual spines. That is, the inter-spine competition for β-catenin determines whether a spine will be matured (increased number of complexes) or pruned (decreased number of complexes). [12] This is a critical mechanism during the refinement of cortical circuitry that occurs throughout development. [11]

Nectin

Nectins are a distinct family of cell adhesion molecules. These CAMs are involved in the initial contact of presynaptic and postsynaptic neuronal processes during synapse formation. There are only four well characterized nectins at the synapse, they are Nectin-1, 2, 3, and 4. [13] All membrane-bound nectins possess an extracellular region with three immunoglobulin-like loops. The furthest loop from the membrane is called the V-type loop and the two loops more interior are C2-type loops. Multiple nectins on one cell membrane will bind together at the V-type loop to form a cluster of nectin proteins, a process called cis-clustering. When two cells possessing individual cis-clusters come into contact they form a strong complex called a trans-interaction which provides adhesion and, in some cases, signaling between the two cells. [14]

The most robust knowledge of nectin’s role in synaptic stabilization comes from the synapses made between mossy fiber terminals and pyramidal cell dendrites in the CA3 region of the hippocampus. [15] The nectins involved in formation and stabilization of this synapse are Nectin-1 and Nectin-3 which protrude from the plasma membrane of the postsynaptic cell and presynaptic cell, respectively, forming heterophilic extracellular contacts. The intracellular domain of all nectins directly bind to a protein called L-Afadin. L-Afadin is an actin binding protein that binds to the F-actin of the actin cytoskeleton. In this way, nectins form ridged connections of the cells actin architecture allowing for the synapse to develop in a controlled and stable environment. [16]

As synapses mature in the CA3 region, nectins and cadherins, which affiliate closely with one another in synaptic stabilization, are shifted to the periphery of the active zone and form the puncta adherens junction (PAJ). The PAJ functions much like the adherens junctions in epithelial tissues. The displacement of these CAMs and the formation of this junction provides the nascent synaptic membranes room to interact and mature while partitioning off the surrounding membrane and providing cytoskeletal fixation. [14]

Neurexin-neuroligin interactions promote synapse stabilization. On the presynaptic side, neurexin associates with synaptotagmin, calcium channels. On the post-synaptic side, neuroligin PDZ domain interacts with scaffolding proteins that help cluster receptor channels. Neurexin-Neuroligin interactions at the synapse.jpg
Neurexin-neuroligin interactions promote synapse stabilization. On the presynaptic side, neurexin associates with synaptotagmin, calcium channels. On the post-synaptic side, neuroligin PDZ domain interacts with scaffolding proteins that help cluster receptor channels.

Neurexin-neuroligin

Neurexin-Neuroligin interactions help establish the trans-synaptic functional asymmetry essential for the stabilization and maintenance of proper synaptic transmission. [17] Presynaptic neurexin and its postsynaptic binding partner, neuroligin, complex early in neural development and are both known to be potent inducers of synaptogenesis. [18] Non-neuronal cells that artificially express neurexin are sufficient to mobilize post-synaptic specializations in co-cultured neurons; [19] neuroligin-expressing cells are likewise able to induce markers of pre-synaptic differentiation in neighboring neurons. [20] [21] However, while both play an important role in synaptogenesis, these cell adhesion molecule are not necessary for formation of neuronal connections during development. [22] A triple knockout mouse mutant of either neurexins or neuroligins exhibit a normal number of synapses but express an embryonic lethal phenotype due to impairment of normal synaptic transmission. [23] Therefore, they are not necessary for synapse formation per se but are essential for the maturation and integration of synapses into the functional circuits necessary for survival.

Beyond their extracellular contact with each other, neurexins and neuroligins also bind intracellularly to a vast network of adaptor proteins and scaffolding structures, which in concert with the actin cytoskeleton, help localize necessary components of synaptic transmission. For example, the first neuroligin (NLGN1) discovered was identified by its PDZ domain which binds to PSD95, a well-known a scaffold protein at glutamatergic synapses that functionally links NMDA receptors to the proper post-synaptic locale. [21] [24] Similarly, another isoform of neuroligin (NLGN2) interacts with gephyrin, a scaffolding protein specific to GABA-ergic synapses, and is responsible for activation of the synaptic adapator protein collybistin. [25] In the case of neurexins, their intracellular binding interactions are equally as important in recruiting the essential machinery for synaptic transmission at the active zone. Like neuroligins, neurexins possess a PDZ-domain that associates with CASK (Calcium-calmodulin-dependent protein kinase). [24] In addition to phosphorylating itself and neurexin, CASK promotes interactions between neurexins and actin binding proteins, thus providing a direct link by which neurexin can modulate cytoskeletal dynamics that is essential for synaptic stability and plasticity. Neurexin can also bind synaptotagmin, a protein embedded in the membrane of synaptic vesicles, and can also promote associations with voltage-gated calcium channel which mediate the ion flux required for neurotransmitter exocytosis upon synaptic stimulation. [26] [23] In this way, neurexin and neuroligin coordinate the morphological and functional aspects of the synapse which in turn permits nascent, immature contacts to stabilize into full-fledged functional platforms for neurotransmission.

Ephrin-Eph signaling

Ephrin A3/EphA4 signaling initiates a cascade of events that results in that regulation of the actin cytoskeleton. Ephrin Signaling.png
Ephrin A3/EphA4 signaling initiates a cascade of events that results in that regulation of the actin cytoskeleton.

Non-traditional adhesion molecules, such as the ephrins, also help stabilize synaptic contacts. Eph receptors and their membrane bound ligands, the ephrins, are involved in a variety of cellular processes during development and maturation including axon guidance, neuronal migration, synaptogenesis, and axon pruning. [27] [28] In the hippocampus, dendritic spine morphology may be regulated by astrocytes via bi-directional ephrin/EphA signaling. [29] Astrocytes and their processes express ephrin A3, whereas the EphA4 receptor is enriched in hippocampal neurons. This interaction, mediated by ephrin A3/EphA4 signaling, induces the recruitment and activation of cyclin-dependent kinase 5 (Cdk5), which then phosphorylates the guanine exchange factor (GEF), ephexin1. [30] Phosphorylated ephexin1 can then activate the small GTPase, RhoA, leading to subsequent activation of its effector, Rho-kinase (ROCK), which results in the rearrangement of actin filaments. [30] Through this mechanism, astrocytic processes are able to stabilize individual dendritic protrusions as well as their maturation into spines via ephrin/EphA signaling. Forward signaling involving the activation of EphA4 results in the stabilization of synaptic proteins at the neuromuscular junction. [30] As in the EphA4/ephrinA3-mediated neuron–glia interaction, this process regulates dynamics of the actin cytoskeleton by activating ROCK through ephexin. [30]

Ephrin B/EphB signaling is also involved in synaptic stabilization through different mechanisms. These molecules contain cytoplasmic tails which interact with scaffolding proteins via their PDZ domains to stabilize newly formed CNS synapses. [28] For example, Ephrin B3 interacts with the adaptor protein glutamate-receptor-interacting protein 1 (GRIP-1) to regulate the development of excitatory dendritic shaft synapses. [28] This process, which was identified in cultures of hippocampal neurons, revealed that Eph/ephrin B3 reverse signaling recruits GRIP1 to the membrane of the postsynaptic shaft. [31] Once at the membrane shaft, GRIP1 helps anchor glutamate receptors below the presynaptic terminal. This process also involves the phosphorylation of a serine residue near the ephrin-B carboxyl terminus (proximal to the PDZ-binding motif) that leads to the stabilization of AMPA receptors at synapses. [27]

Another mechanism, found in hippocampal neurons, revealed that EphB signaling could promote spine maturation by modulating Rho GTPase activity, as observed with EphAs. [32] Unlike EphAs, however, the EphB2 receptor has been shown to interact with the postsynaptic N-methyl-D-aspartate receptors (NMDARs) to recruit the GEF Tiam1 to the complex upon ephrinB binding. [32] [30] [33] Phosphorylation of Tiam1 occurs in response to NMDAR activity, which allows for the influx of calcium that activates Tiam1. This mechanism also results in the modulation of the actin cytoskeleton. As a result of this stabilization, both EphB2 forward signaling and ephrin-B3 reverse signaling has been found to induce LTP via NMDARs. [34]

Related Research Articles

<span class="mw-page-title-main">Dendritic spine</span> Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

<span class="mw-page-title-main">Juxtacrine signalling</span> Contact-based cell-cell signalling

In biology, juxtacrine signalling is a type of cell–cell or cell–extracellular matrix signalling in multicellular organisms that requires close contact. In this type of signalling, a ligand on one surface binds to a receptor on another adjacent surface. Hence, this stands in contrast to releasing a signaling molecule by diffusion into extracellular space, the use of long-range conduits like membrane nanotubes and cytonemes or the use of extracellular vesicles like exosomes or microvesicles. There are three types of juxtacrine signaling:

  1. A membrane-bound ligand and a membrane protein of two adjacent cells interact.
  2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
  3. An extracellular matrix glycoprotein and a membrane protein interact.
<span class="mw-page-title-main">Postsynaptic density</span>

The postsynaptic density (PSD) is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in close apposition to the presynaptic active zone and ensures that receptors are in close proximity to presynaptic neurotransmitter release sites. PSDs vary in size and composition among brain regions, and have been studied in great detail at glutamatergic synapses. Hundreds of proteins have been identified in the postsynaptic density, including glutamate receptors, scaffold proteins, and many signaling molecules.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

The synaptotropic hypothesis, also called the synaptotrophic hypothesis, is a neurobiological hypothesis of neuronal growth and synapse formation. The hypothesis was first formulated by J.E. Vaughn in 1988, and remains a focus of current research efforts. The synaptotropic hypothesis proposes that input from a presynaptic to a postsynaptic cell eventually can change the course of synapse formation at dendritic and axonal arbors. This synapse formation is required for the development of neuronal structure in the functioning brain.

Synaptojanin is a protein involved in vesicle uncoating in neurons. This is an important regulatory lipid phosphatase. It dephosphorylates the D-5 position phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Phosphatidylinositol (4,5)-bisphosphate(PIP2). It belongs to family of 5-phosphatases, which are structurally unrelated to D-3 inositol phosphatases like PTEN. Other members of the family of 5'phosphoinositide phosphatases include OCRL, SHIP1, SHIP2, INPP5J, INPP5E, INPP5B, INPP5A and SKIP.

<span class="mw-page-title-main">Neurexin</span> Protein family

Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.

<span class="mw-page-title-main">PTPRT</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.

<span class="mw-page-title-main">Neuroligin</span> Protein

Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse. Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures. Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis. In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders. Antibodies in a mother from previous male pregnancies against neuroligin 4 from the Y chromosome increase the probability of homosexuality in male offspring.

Nectins and Nectin-like molecules (Necl) are families of cellular adhesion molecules involved in Ca2+-independent cellular adhesion.

Collybistin is a protein identified as a regulator of the localization of gephyrin, inducing the formation of submembrane gephyrin aggregates that accumulate glycine and GABA receptors. In 2000 it was identified as a gephyrin binding partner, and an important determinant of inhibitory postsynaptic membrane formation and plasticity. Gephyrin and collybistin are recruited to developing postsynaptic membranes of inhibitory synapses by the trans-synaptic adhesion molecule neuroligin-2, where they provide the scaffold for the clustering of inhibitory postsynaptic receptors to form a functioning inhibitory synapse.

Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.

Target selection is the process by which axons selectively target other cells for synapse formation. Synapses are structures which enable electrical or chemical signals to pass between nerves. While the mechanisms governing target specificity remain incompletely understood, it has been shown in many organisms that a combination of genetic and activity-based mechanisms govern initial target selection and refinement. The process of target selection has multiple steps that include Axon pathfinding when neurons extend processes to specific regions, cellular target selection when neurons choose appropriate partners in a target region from a multitude of potential partners, and subcellular target selection where axons often target particular regions of a partner neuron.

References

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