Synaptic pruning

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A model view of the synapse SynapseSchematic en.svg
A model view of the synapse

Synaptic pruning, a phase in the development of the nervous system, is the process of synapse elimination that occurs between early childhood and the onset of puberty in many mammals, including humans. [1] Pruning starts near the time of birth and continues into the late-20s. [2] During pruning, both the axon and dendrite decay and die off. It was traditionally considered to be complete by the time of sexual maturation, but this was discounted by MRI studies. [3]

Contents

The infant brain will increase in size by a factor of up to 5 by adulthood, reaching a final size of approximately 86 (± 8) billion neurons. [4] Two factors contribute to this growth: the growth of synaptic connections between neurons and the myelination of nerve fibers; the total number of neurons, however, remains the same. After adolescence, the volume of the synaptic connections decreases again due to synaptic pruning. [5]

Pruning is influenced by environmental factors and is widely thought to represent learning. [5]

Variations

Regulatory pruning

At birth, the neurons in the visual and motor cortices have connections to the superior colliculus, spinal cord, and pons. The neurons in each cortex are selectively pruned, leaving connections that are made with the functionally appropriate processing centers. Therefore, the neurons in the visual cortex prune the synapses with neurons in the spinal cord, and the motor cortex severs connections with the superior colliculus. This variation of pruning is known as large-scaled stereotyped axon pruning. Neurons send long axon branches to appropriate and inappropriate target areas, and the inappropriate connections are eventually pruned away. [6]

Regressive events refine the abundance of connections, seen in neurogenesis, to create a specific and mature circuitry. Apoptosis and pruning are the two main methods of severing the undesired connections. In apoptosis, the neuron is killed and all connections associated with the neuron are also eliminated. In contrast, the neuron does not die in pruning, but requires the retraction of axons from synaptic connections that are not functionally appropriate.

It is believed that the purpose of synaptic pruning is to remove unnecessary neuronal structures from the brain; as the human brain develops, the need to understand more complex structures becomes much more pertinent, and simpler associations formed at childhood are thought to be replaced by complex structures. [7]

Despite the fact it has several connotations with regulation of cognitive childhood development, pruning is thought to be a process of removing neurons which may have become damaged or degraded in order to further improve the "networking" capacity of a particular area of the brain. [7] Furthermore, it has been stipulated that the mechanism not only works in regard to development and reparation, but also as a means of continually maintaining more efficient brain function by removing neurons by their synaptic efficiency. [7]

Pruning in the maturing brain

The pruning that is associated with learning is known as small-scale axon terminal arbor pruning. Axons extend short axon terminal arbors toward neurons within a target area. Certain terminal arbors are pruned by competition. The selection of the pruned terminal arbors follow the "use it or lose it" principle seen in synaptic plasticity. This means synapses that are frequently used have strong connections while the rarely used synapses are eliminated. Examples seen in vertebrate include pruning of axon terminals in the neuromuscular junction in the peripheral nervous system and the pruning of climbing fiber inputs to the cerebellum in the central nervous system. [6]

In terms of humans, synaptic pruning has been observed through the inference of differences in the estimated numbers of glial cells and neurons between children and adults, which differs greatly in the mediodorsal thalamic nucleus.

In a study conducted in 2007 by Oxford University, researchers compared 8 newborn human brains with those of 8 adults using estimates based upon size and evidence gathered from stereological fractionation. They showed that, on average, estimates of adult neuron populations were 41% lower than those of the newborns in the region they measured, the mediodorsal thalamic nucleus. [8]

However, in terms of glial cells, adults had far larger estimates than those in newborns; 36.3 million on average in adult brains, compared to 10.6 million in the newborn samples. [8] The structure of the brain is thought to change when degeneration and deafferentation occur in postnatal situations, although these phenomena have not been observed in some studies. [8] In the case of development, neurons which are in the process of loss via programmed cell death are unlikely to be re-used, but rather replaced by new neuronal structures or synaptic structures, and have been found to occur alongside the structural change in the sub-cortical gray matter.

Synaptic pruning is classified separately from the regressive events seen during older ages. While developmental pruning is experience dependent, the deteriorating connections that are synonymous with old age are not. The stereotyped pruning can be compared to the process of chiseling and molding of stone into a statue. Once the statue is complete, the weather will begin to erode the statue and this represents the experience-independent deletion of connections.

Forgetting problems with learning through pruning

All attempts to construct artificial intelligence systems that learn by pruning connections that are disused have the problem that every time they learn something new, they forget everything they learned before. Since biological brains follow the same laws of physics as artificial intelligences, as all physical objects do, these researchers argue that if biological brains learned by pruning they would face the same catastrophic forgetting issues. This is pointed out as an especially severe problem if the learning is supposed to be part of a developmental process since retention of older knowledge is necessary for developmental types of learning, and as such it is argued that synaptic pruning cannot be a mechanism of mental development. It is argued that developmental types of learning must use other mechanisms that do not rely on synaptic pruning. [9] [10]

Energy saving for reproduction and discontinuous differences

One theory of why many brains are synaptically pruned when a human or other primate grows up is that maintenance of synapses consume nutrients which may be needed elsewhere in the body during growth and sexual maturation. This theory presupposes no mental function of synaptic pruning. The empirical observation that human brains fall into two distinct categories, one that reduces synaptic density by about 41% while growing up and another synaptically neotenic type in which there is very little to no reduction of synaptic density, but no continuum between them,[ citation needed ] is explainable by this theory as an adaptation to physiologies with different nutritional needs in which one type needs to free up nutrients to get through puberty while the other can mature sexually by other redirections of nutrients that do not involve reducing the brain's consumption of nutrients. Citing that most of the nutrient costs in the brain are in maintaining the brain cells and their synapses, rather than the firing itself, this theory explains the observation that some brains appear to continue pruning years after sexual maturation as a result of some brains having more robust synapses, allowing them to take years of neglect before the synaptic spines finally disintegrate. Another hypothesis that can explain the discontinuity is that of limited functional genetic space restricted by the fact that most of the human genome needs to lack sequence-specific functions to avoid too many deleterious mutations, predicting that evolution proceeds by a few of the mutations happening to have large effects while most mutations do not have any effects at all. [11] [12]

Mechanisms

The three models explaining synaptic pruning are axon degeneration, axon retraction, and axon shedding. In all cases, the synapses are formed by a transient axon terminal, and synapse elimination is caused by the axon pruning. Each model offers a different method in which the axon is removed to delete the synapse. In small-scale axon arbor pruning, neural activity is thought to be an important regulator,[ citation needed ] but the molecular mechanism remains unclear. Hormones and trophic factors are thought to be the main extrinsic factors regulating large-scale stereotyped axon pruning. [6]

Axon degeneration

In Drosophila , there are extensive changes made to the nervous system during metamorphosis. Metamorphosis is triggered by ecdysone, and during this period, extensive pruning and reorganization of the neural network occurs. Therefore, it is theorized that pruning in Drosophila is triggered by the activation of ecdysone receptors. Denervation studies at the neuromuscular junction of vertebrates have shown that the axon removal mechanism closely resembles Wallerian degeneration. [13] However, the global and simultaneous pruning seen in Drosophilia differs from the mammalian nervous system pruning, which occurs locally and over multiple stages of development. [6]

Axon retraction

Axon branches retract in a distal to proximal manner. The axonal contents that are retracted are thought to be recycled to other parts of the axon. The biological mechanism with which axonal pruning occurs still remains unclear for the mammalian central nervous system. However, pruning has been associated with guidance molecules in mice. Guidance molecules serve to control axon pathfinding through repulsion, and also initiate pruning of exuberant synaptic connections. Semaphorin ligands and the receptors neuropilins and plexins are used to induce retraction of the axons to initiate hippocampo-septal and infrapyramidal bundle (IPB) pruning. Stereotyped pruning of the hippocampal projections have been found to be significantly impaired in mice that have a Plexin-A3 defect. Specifically, axons that are connected to a transient target will retract once the Plexin-A3 receptors are activated by class 3 semaphorin ligands. In IPB, the expression of mRNA for Sema3F is present in the hippocampus prenatally, lost postnatally and returns in the stratum oriens. Coincidentally, onset IPB pruning occurs around the same time. In the case of the hippocampal-septal projections, expression of mRNA for Sema3A was followed by the initiation of pruning after 3 days. This suggests that pruning is triggered once the ligand reaches threshold protein levels within a few days after detectable mRNA expression. [14] Pruning of axons along the visual corticospinal tract (CST) is defective in neuropilin-2 mutants and plexin-A3 and plexin-A4 double mutant mice. Sema3F is also expressed in the dorsal spinal cord during the pruning process. There is no motor CST pruning defect observed in these mutants. [6]

Stereotyped pruning has also been observed in the tailoring of overextended axon branches from the retinotopy formation. Ephrin and the ephrin receptors, Eph, have been found to regulate and direct retinal axon branches. Forward signaling between ephrin-A and EphA, along the anterior-posterior axis, has been found to inhibit retinal axon branch formation posterior to a terminal zone. The forward signaling also promotes pruning of the axons that have reached into the terminal zone. However, it remains unclear whether the retraction mechanism seen in IPB pruning is applied in retinal axons. [15]

Reverse signaling between ephrin-B proteins and their Eph receptor tyrosine kinases have been found to initiate the retraction mechanism in the IPB. Ephrin-B3 is observed to transduce tyrosine phosphorylation-dependent reverse signals into hippocampal axons that trigger pruning of excessive IPB fibers. The proposed pathway involves EphB being expressed on the surface of target cells that results in tyrosine phosphorylation of ephrin-B3. Ensuing binding of ephrin-B3 to the cytoplasmic adaptor protein, Grb4, leads to the recruitment and binding of Dock180 and p21 activated kinases (PAK). The binding of Dock180 increases Rac-GTP levels, and PAK mediates the downstream signaling of active Rac that leads to the retraction of the axon and eventual pruning. [16]

Axon shedding

Time-lapse imaging of retreating axons in neuromuscular junctions of mice have shown axonal shedding as a possible mechanism of pruning. The retreating axon moved in a distal to proximal order and resembled retraction. However, there were many cases in which remnants were shed as the axons were retracting. The remnants, named axosomes, contained the same organelles seen in the bulbs attached to the end of axons and were commonly found around the proximity of the bulbs. This indicates that axosomes are derived from the bulbs. Furthermore, axosomes did not have electron-dense cytoplasms or disrupted mitochondria indicating that they were not formed through Wallerian degeneration. [17]

Potential role in schizophrenia

Synaptic pruning has been suggested to have a role in the pathology of neurodevelopmental disorders such as schizophrenia, as well as in autism spectrum disorder. [18] [19]

Microglia have been implicated in synaptic pruning, as they have roles in both the immune response as macrophages as well as in neuronal upkeep and synaptic plasticity in the CNS during fetal development, early postnatal development, and adolescence, in which they engulf unneeded or redundant synapses via phagocytosis. [18] Microglial synapse engulfment and uptake has been specifically observed to be upregulated in the isolated synaptosomes of male patients with schizophrenia compared to healthy controls, suggesting upregulated microglia-induced synaptic pruning in these individuals. Microglia-mediated synaptic pruning has also been observed to be upregulated during late adolescence and early adulthood, which could also account for the age of onset for schizophrenia often being reported around this time in development (late teens to early 20s for men, and mid-to-late 20s for women) [20] The drug minocycline, a semisynthetic brain-penetrant tetracycline antibiotic, has been found to somewhat reverse these changes made to patient synaptosomes by downregulating synaptic pruning. [20]

Genes in the Complement Component 4 (C4) locus of the major histocompatibility complex (MHC), which encode for complement factors, have also been tied to schizophrenia risk through gene linkage studies. [20] The fact that some of these complement factors are involved in signaling during synaptic pruning also seems to suggest that schizophrenia risk may be linked to synaptic pruning. [19] Specifically, complement factors C1q and C3 have been found to have a role in microglia-mediated synaptic pruning. [19] Carriers of C4 risk variants have also been found to be tied to this kind of synapse overpruning in microglia. [20] The proposed mechanism for this interaction is increased complement factor C3 deposition onto synaptosomes as a consequence of increased C4A expression in these risk variant carriers. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon, or nerve fiber, is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Dendrite</span> 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.

<span class="mw-page-title-main">Neuron</span> Electrically excitable cell found in the nervous system of animals

A neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials. Neurons communicate with other cells via synapses - specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. Non-animals like plants and fungi do not have nerve cells.

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

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.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

<span class="mw-page-title-main">Neural circuit</span> Network or circuit of neurons

A neural circuit is a population of neurons interconnected by synapses to carry out a specific function when activated. Multiple neural circuits interconnect with one another to form large scale brain networks.

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.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

The development of the nervous system in humans, or neural development or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience to describe the cellular and molecular mechanisms by which the complex nervous system forms in humans, develops during prenatal development, and continues to develop postnatally.

Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.

<span class="mw-page-title-main">Axon terminal</span>

Axon terminals are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses called action potentials away from the neuron's cell body, or soma, in order to transmit those impulses to other neurons, muscle cells or glands.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

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.

Developmental plasticity is a general term referring to changes in neural connections during development as a result of environmental interactions as well as neural changes induced by learning. Much like neuroplasticity, or brain plasticity, developmental plasticity is specific to the change in neurons and synaptic connections as a consequence of developmental processes. A child creates most of these connections from birth to early childhood. There are three primary methods by which this may occur as the brain develops, but critical periods determine when lasting changes may form. Developmental plasticity may also be used in place of the term phenotypic plasticity when an organism in an embryonic or larval stage can alter its phenotype based on environmental factors. However, a main difference between the two is that phenotypic plasticity experienced during adulthood can be reversible, whereas traits that are considered developmentally plastic set foundations during early development that remain throughout the life of the organism.

<span class="mw-page-title-main">Tropic cues involved in growth cone guidance</span>

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

Beth Stevens is an associate professor in the Department of Neurology at Harvard Medical School and the F. M. Kirby Neurobiology Center at Boston Children’s Hospital. She has helped to identify the role of microglia and complement proteins in the "pruning" or removal of synaptic cells during brain development, and has also determined that the impaired or abnormal microglial function could be responsible for diseases like autism, schizophrenia, and Alzheimer's.

<span class="mw-page-title-main">Synaptic stabilization</span> 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.

Dorothy P. "Dori" Schafer is an assistant professor in the department of neurobiology at University of Massachusetts Medical School. Her research focuses on the role of microglia in the development of synapses and brain circuits as well as the maintenance of synaptic plasticity.

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

References

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  10. ↑ Gul Muhammad Khan (2017). "Evolution of Artificial Neural Development: In search of learning genes"
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  12. ↑ P. Michael Conn (2011)."Handbook of Models for Human Aging"
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