Synaptotropic hypothesis

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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, [1] and remains a focus of current research efforts. [2] The synaptotropic hypothesis proposes that input from a presynaptic to a postsynaptic cell (and maturation of excitatory synaptic inputs) 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. [2]

Contents

Dendritic Arbor Development

Growth

Dendrites of central nervous system neurons grow by addition and retraction of thin branches. This process is highly dynamic. Only a small fraction of newly added branches are actually maintained to become long-lasting components of the arbor. This process suggests that the branches sample the environment to detect the appropriate cells with which to form synapses. [2] As a result, the hypothesis predicts that growth will be directed into regions containing more presynaptic elements. [1] This morphology can be stabilized by creating microtubule nucleation at the microtubules. [2]

Synaptogenesis

The formation of new synapses begins with initial contact between cells via cell-cell adhesion. This contact often occurs between either axonal or dendritic filopodia, which are highly dynamic and rarely stabilize. Next, the adhesive contact is converted to a nascent synapse, which contains glutamatergic NMDA receptors, but not AMPA receptors. However, the activation of NMDARs by glutamate can trigger the recruitment of AMPARs from the postsynaptic density. They also have a relatively high concentration of dense-core vesicles, which are thought to deliver structural proteins to the presynaptic site. [2]

Synapse Maturation

Maturation of glutamatergic synapses involves changes in the amplitude of AMPA receptor-mediated synaptic transmission, as well as in the NMDAR subunit composition. Further, it includes the assembly of the postsynaptic density, which is a protein-dense region with both structural and signaling functions. Synaptic vesicles are also recruited, resulting in an increase in the reliability of synaptic transmission. [2]

Neuronal Architecture

Although neurons generally follow a basic morphological pattern (consisting of the tree-like dendritic arbor, a cell body, and an axonal output), the number of pre-and post-synaptic elements are unique to every neuron and are central to understanding their complex neural function.

The synaptotropic hypothesis implies that function drives form, since the appropriateness of new synapses is constantly being tested by the filopodia in the first stages of dendritogenesis, thus determining the form of the neural architecture. [3]

Modifications of the Hypothesis

Some interpret the synaptotropic hypothesis as saying that manipulations that increase synapse formation and maturation promote formation of larger dendritic arbors, while treatments that reduce synapse maturation result in smaller arbors. However, the opposite result has been found in different manipulations of the molecular pathways underlying synaptogeneis. A resulting modified version of the hypothesis has emerged “in which graded levels of synaptic maturation produce corresponding levels of stabilization”. [3] This is a different way of viewing the synaptotropic hypothesis that still takes into account the molecular mechanisms of dendritogenesis and synaptogenesis.

Supporting Evidence

The synaptotropic hypothesis would predict that cell adhesion molecules that are important in synapse formation would also greatly affect dendritic arbor growth. This has been shown to be the case with cadherins. [4]

When peptides that mimic the cytoplasmic tails of AMPA receptors are expressed in individual Xenopus neurons, trafficking of AMPA receptors to nascent synapses is minimized in those cells. These cells, like normal neurons, extend and retract dendritic branches. In the normal cell, some of these branches would form synapses, which is not the case in the neurons expressing the peptide. As a result, these cells have minimal dendritic arbors. [5] This is because without AMPA receptors, the neuron can't cause neighboring neurons to fire action potentials, therefore disallowing their synapses to strengthen.

As described previously, the pattern of dendritic branching depends on the initial contact of filopodia with afferent axons. The hypothesis predicts that regions with numerous prospective presynaptic terminals will attract more growing dendrites. Researchers have used the developing mouse spinal cord to test this hypothesis. A computer-assisted three-dimensional reconstruction system has been used with Golgi's method preparations of mouse spinal cords. The relative dendritic lengths and densities at various zones in the spinal cord indicate that dendritic growth is initially primarily towards the marginal zone (because of synaptogenic presynaptic terminals). However, this biased distribution is lost as synapses form in the intermediate zone. This study is consistent with predictions of the synaptotropic hypothesis of dendritic branching. [1]

Dissenting Evidence

Evidence against the synaptotropic hypothesis comes from experiments with “munc 18 knock-out mice”, mice engineered to be missing the Munc 18-1 protein, without which the mice never release neurotransmitters from synaptic vesicles. Despite this, the mice develop normal brains before dying immediately after birth. [2]

Imaging Techniques

Dynamic Morphometrics

Dynamic morphometrics technology involves new methods of labeling, imaging, and quantifying dendritogenesis. The transparent, externally developing vertebrate embryos of Xenopus laevis and zebrafish allow direct imaging of the organism in the critical stages of development while keeping the embryos intact. Individual brain neurons can be fluorescently labeled using single cell electroporation while leaving the rest of the brain unaltered. Also, two-photon microscopy allows in vivo time-lapse imaging to create high-resolution, 3D images of neurons deep within the living brain, again with minimal damage to the brain. New computer software also can now track and measure dendritic growth. [3] These methods comprise a new type of imaging technology that can monitor the process of dendritogenesis and can help give evidence to either dissent with or support the synaptotropic hypothesis.

Applications

Dynamic morphometrics and other imaging techniques have been used to observe both dendrite growth and synaptogenesis—two processes between which the relationship is not well understood. Non-spiny dendritic arbors expressing a fluorescent postsynaptic marker protein were imaged as they arborized (in the zebrafish larvae), and this confirmed the role of newly extended dendritic filopodia in synaptogenesis, their maturation into dendritic branches, and the result, namely, growth and branching of the dendritic arbor. [1] These findings support the model wherein synapse formation can direct dendrite arborization, a basic tenet of the synaptotropic hypothesis.

Related Research Articles

Dendrite Small projection on a neuron that receive signals

Dendrites, also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. Electrical stimulation is transmitted onto dendrites by upstream neurons via synapses which are located at various points throughout the dendritic tree. Dendrites play a critical role in integrating these synaptic inputs and in determining the extent to which action potentials are produced by the neuron. Dendritic arborization, also known as dendritic branching, is a multi-step biological process by which neurons form new dendritic trees and branches to create new synapses. The morphology of dendrites such as branch density and grouping patterns are highly correlated to the function of the neuron. Malformation of dendrites is also tightly correlated to impaired nervous system function. Some disorders that are associated with the malformation of dendrites are autism, depression, schizophrenia, Down syndrome and anxiety.

Neuron Electrically excitable cell that communicates via synapses

A neuron or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. It is the main component of nervous tissue in all animals except sponges and placozoa. Plants and fungi do not have nerve cells.

Chemical synapse Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

Dendritic spine 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.

Long-term potentiation Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

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.

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

Excitatory 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 travel, each neuron often making numerous connections with other cells. 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.

Schaffer collaterals are axon collaterals given off by CA3 pyramidal cells in the hippocampus. These collaterals project to area CA1 of the hippocampus and are an integral part of memory formation and the emotional network of the Papez circuit, and of the hippocampal trisynaptic loop. It is one of the most studied synapses in the world and named after the Hungarian anatomist-neurologist Károly Schaffer.

An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.

Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of individual synapses. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in memory and learning such as long-term potentiation (LTP), long-term depression (LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamines, and the pool of hormones affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured hippocampus cells or hippocampal slices.

Synapse Structure of 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.

Cellular neuroscience is a branch of neuroscience concerned with the study of neurons at a cellular level. This includes morphology and physiological properties of single neurons. Several techniques such as intracellular recording, patch-clamp, and voltage-clamp technique, pharmacology, confocal imaging, molecular biology, two photon laser scanning microscopy and Ca2+ imaging have been used to study activity at the cellular level. Cellular neuroscience examines the various types of neurons, the functions of different neurons, the influence of neurons upon each other, and how neurons work together.

Nonsynaptic plasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

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 spines. 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 lead to the formation of new synapses as well as increased cell communication.

Dendrodendritic synapses are connections between the dendrites of two different neurons. This is in contrast to the more common axodendritic synapse (chemical synapse) where the axon sends signals and the dendrite receives them. Dendrodendritic synapses are activated in a similar fashion to axodendritic synapses in respects to using a chemical synapse. An incoming action potential permits the release of neurotransmitters to propagate the signal to the post synaptic cell. There is evidence that these synapses are bi-directional, in that either dendrite can signal at that synapse. Ordinarily, one of the dendrites will display inhibitory effects while the other will display excitatory effects. The actual signaling mechanism utilizes Na+ and Ca2+ pumps in a similar manner to those found in axodendritic synapses.

Synaptic stabilization Modifying synaptic strength via 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. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to 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.

An axo-axonic synapse is a type of synapse, formed by one neuron projecting its axon terminals onto another neuron’s axon.

References

  1. 1 2 3 4 Vaughn, James E.; Barber, Robert P.; Sims, Terry J. (1988). "Dendritic development and preferential growth into synaptogenic fields: A quantitative study of Golgi-impregnated spinal motor neurons". Synapse. 2 (1): 69–78. doi:10.1002/syn.890020110. PMID   2458630. S2CID   31184444.
  2. 1 2 3 4 5 6 7 Cline, Hollis; Haas, Kurt (2008). "The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis". The Journal of Physiology. 586 (6): 1509–17. doi:10.1113/jphysiol.2007.150029. PMC   2375708 . PMID   18202093.
  3. 1 2 3 Chen, Simon Xuan; Haas, Kurt (2011). "Function directs form of neuronal architecture". BioArchitecture. 1 (1): 2–4. doi:10.4161/bioa.1.1.14429. PMC   3158632 . PMID   21866253.
  4. ↑ Ye, B; Jan, Y (2005). "The cadherin superfamily and dendrite development". Trends in Cell Biology. 15 (2): 64–7. doi:10.1016/j.tcb.2004.12.003. PMID   15695092.
  5. ↑ Cline, Holly T. (June 19, 2009). Building Brain Circuits. Friday Evening Lecture Series. Marine Biological Laboratory.
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