Synaptic pruning
Encyclopedia
In neuroscience
, synaptic pruning, neuronal pruning or axon pruning refer to neurological regulatory processes, which facilitate a change in neural structure by reducing the overall number of neurons or connections, leaving more efficient synaptic configurations. Pruning is a neurological regulatory process that is a general feature of mammalian neurological development. Pruning starts near the time of birth and is completed by the time of sexual maturation in humans. At birth, the human brain consists of approximately 10 billion neurons.The infant brain will increase in size by a factor of up to 5 by adulthood. Two factors contribute to this growth: the growth of synaptic connections between neurons, and the myelination of nerve fibers. Generally, the number of neurons in the cortex increases until adolescence reflecting a growth of synapses. A decrease in synapses is seen after adolescence reflecting synaptic pruning, and approximately 50% of neurons during development do not survive until adulthood. Pruning is influenced by environmental factors and is widely thought of to represent learning.
, 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.
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.
The purpose of synaptic pruning is believed to be 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.
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. 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.
s and neurons between children and adults, which differs greatly in the area of the mediodorsal thalamus.
In a study conducted in 2007 by Oxford University, it was found that by comparing 8 newborn human brains with those of 8 adult brains using estimates based upon size and gathering from stereological
fractionation, showed that on average, adult neuron estimates were 41% lower than those of the newborn.
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. 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. 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 related to the 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.
, but is mostly prevalent in developing invertebrates.
, and during this period, extensive pruning and reorganization of the neural network occurs. Therefore it is theorized that pruning in Drosophilia are triggered by the activation of ecdysone receptors. The pruning seen in Drosophilia has been shown to share the same characteristics with Wallerian degeneration
in vertebrates. 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.
(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.
Stereotyped pruning has also been observed in the tailoring of overextended axon branches from the formation of the retinotopic map. Ephrin and their 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.
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.
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, synaptic pruning, neuronal pruning or axon pruning refer to neurological regulatory processes, which facilitate a change in neural structure by reducing the overall number of neurons or connections, leaving more efficient synaptic configurations. Pruning is a neurological regulatory process that is a general feature of mammalian neurological development. Pruning starts near the time of birth and is completed by the time of sexual maturation in humans. At birth, the human brain consists of approximately 10 billion neurons.The infant brain will increase in size by a factor of up to 5 by adulthood. Two factors contribute to this growth: the growth of synaptic connections between neurons, and the myelination of nerve fibers. Generally, the number of neurons in the cortex increases until adolescence reflecting a growth of synapses. A decrease in synapses is seen after adolescence reflecting synaptic pruning, and approximately 50% of neurons during development do not survive until adulthood. Pruning is influenced by environmental factors and is widely thought of to represent learning.
Regulatory and regenerative purpose
At birth, the neurons in the visual and motor cortices have connections to the superior colliculusSuperior colliculus
The optic tectum or simply tectum is a paired structure that forms a major component of the vertebrate midbrain. In mammals this structure is more commonly called the superior colliculus , but, even in mammals, the adjective tectal is commonly used. The tectum is a layered structure, with a...
, spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, and pons
Pons
The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...
. 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.
Regressive events refine the abundance of connections, seen in neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
, to create a specific and mature circuitry. Apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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.
The purpose of synaptic pruning is believed to be 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.
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. 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.
During maturation phases in humans
In terms of humans, synaptic pruning has been observed through the inference of differences in the estimated numbers of glial cellGlial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s and neurons between children and adults, which differs greatly in the area of the mediodorsal thalamus.
In a study conducted in 2007 by Oxford University, it was found that by comparing 8 newborn human brains with those of 8 adult brains using estimates based upon size and gathering from stereological
Stereology
Stereology was originally defined as "the spatial interpretation of sections". It is an interdisciplinary field that is largely concerned with the three-dimensional interpretation of planar sections of materials or tissues...
fractionation, showed that on average, adult neuron estimates were 41% lower than those of the newborn.
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. The structure of the brain is thought to change when degeneration
Degenerative disease
A degenerative disease, also called neurodegenerative disease, is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...
and deafferentation occur in postnatal situations, although these phenomena have not been observed in some studies. 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
Gray Matter
"Gray Matter" is a short story by Stephen King, first published in the October 1973 issue of Cavalier magazine, and later collected in King's 1978 collection Night Shift. It is set in the same area as King's novel Dreamcatcher.-Setting:...
.
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 related to the 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.
Overview
The three main proposed models explaining axon removal during synapse pruning are axon retraction, removal, and shedding. The removal model is similar to Wallerian degenerationWallerian degeneration
Wallerian degeneration is a process that results when a nerve fiber is cut or crushed, in which the part of the axon separated from the neuron's cell body degenerates distal to the injury. This is also known as anterograde degeneration, or orthograde degeneration...
, but is mostly prevalent in developing invertebrates.
Removal
In Drosophilia, there are extensive changes made to the nervous system during metamorphosis. Metamorphosis is triggered by ecdysoneEcdysone
Ecdysone is a steroidal prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. Insect molting hormones are generally called ecdysteroids. Ecdysteroids act as moulting hormones of arthropods but also occur in other related phyla where they...
, and during this period, extensive pruning and reorganization of the neural network occurs. Therefore it is theorized that pruning in Drosophilia are triggered by the activation of ecdysone receptors. The pruning seen in Drosophilia has been shown to share the same characteristics with Wallerian degeneration
Wallerian degeneration
Wallerian degeneration is a process that results when a nerve fiber is cut or crushed, in which the part of the axon separated from the neuron's cell body degenerates distal to the injury. This is also known as anterograde degeneration, or orthograde degeneration...
in vertebrates. 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.
Retraction
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 projetions, 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 a threshold protein levels within a few days after detectable mRNA expression. Pruning of axons along the visual corticospinal tractCorticospinal tract
The corticospinal or pyramidal tract is a collection of axons that travel between the cerebral cortex of the brain and the spinal cord....
(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.
Stereotyped pruning has also been observed in the tailoring of overextended axon branches from the formation of the retinotopic map. Ephrin and their 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.
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
P21 activated kinases
p21 activated kinases are members of a family of enzymes. They serve as targets for the small GTP binding proteins CDC42 and Rac and have been implicated in a wide range of biological activities.Members include:...
(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.