
Synaptic pruning is the process of
synapse
In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
elimination or weakening.
Though it occurs throughout the lifespan of a mammal, the most active period of synaptic pruning in the
development of the nervous system
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 ...
occurs between early childhood and the onset of puberty in many
mammal
A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
s, including
human
Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
s.
Pruning starts near the time of birth and continues into the late-20s. During elimination of a synapse, the
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
withdraws or dies off, and the
dendrite
A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...
decays and die off. Synaptic pruning was traditionally considered to be complete by the time of
sexual maturation, but
magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
studies have discounted this idea.
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. The total number of neurons, however, remains approximately the same, containing approximately 86 (± 8) billion
neurons
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
.
After adolescence, the volume of the synaptic connections decreases again due to synaptic pruning.
Pruning is influenced by environmental factors. For instance, if the eyes are sewn shut in the critical period when synaptic pruning of the
retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
takes place, the lack of input of light will cause the synaptic connections required for vision to die off, resulting in
blindness
Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...
.
Variations
Regulatory pruning
At birth, the neurons in the visual and motor cortices have connections to the
superior colliculus
In neuroanatomy, the superior colliculus () is a structure lying on the tectum, roof of the mammalian midbrain. In non-mammalian vertebrates, the Homology (biology), homologous structure is known as the optic tectum or optic lobe. The adjective f ...
,
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
, and
pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other mammals, lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of ...
. 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
The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalam ...
prune the synapses with neurons in the spinal cord, and the
motor cortex
The motor cortex is the region of the cerebral cortex involved in the planning, motor control, control, and execution of voluntary movements.
The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately ...
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.
Regressive events refine the abundance of connections, seen in
neurogenesis
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
, to create a specific and mature circuitry.
Apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
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
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
s 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.
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.
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
In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
. 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
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
in the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
and the pruning of
climbing fiber inputs to the cerebellum in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
.
In terms of humans, synaptic pruning has been observed through the inference of differences in the estimated numbers of
glial cell
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
s and neurons between children and adults, which differs greatly in the
mediodorsal thalamic nucleus.
In a study conducted in 2007 by
Oxford University
The University of Oxford is a collegiate research university in Oxford, England. There is evidence of teaching as early as 1096, making it the oldest university in the English-speaking world and the second-oldest continuously operating u ...
, researchers compared 8 newborn human brains with those of 8 adults using estimates based upon size and evidence gathered from
stereological fractionation
Fractionation is a separation process in which a certain quantity of a mixture (of gasses, solids, liquids, enzymes, or isotopes, or a suspension) is divided during a phase transition, into a number of smaller quantities (fractions) in which t ...
. 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.
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 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
Artificial intelligence (AI) is the capability of computer, computational systems to perform tasks typically associated with human intelligence, such as learning, reasoning, problem-solving, perception, and decision-making. It is a field of re ...
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.
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
nutrient
A nutrient is a substance used by an organism to survive, grow and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s 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, 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.
[P. Michael Conn (2011)."Handbook of Models for Human Aging"]
Mechanisms
The three models explaining synaptic pruning are axon degeneration, axon retraction, and axon shedding. In all cases, the
synapses
In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
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, but the molecular mechanism remains unclear.
Hormones
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...
and
trophic factors are thought to be the main extrinsic factors regulating large-scale stereotyped axon pruning.
Axon degeneration
In ''
Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
'', there are extensive changes made to the nervous system during
metamorphosis
Metamorphosis is a biological process by which an animal physically develops including birth transformation or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and different ...
. 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.
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.
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
Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor (biochemistry), recepto ...
ligands
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
and the receptors
neuropilins and
plexins
A plexin is a protein which acts as a Receptor (biochemistry), receptor for semaphorin family signaling proteins. It is classically known for its expression on the surface of axon growth cones and involvement in signal transduction to steer axon ...
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
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
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
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
expression.
Pruning of axons along the visual
corticospinal tract
The corticospinal tract is a white matter motor pathway starting at the cerebral cortex that terminates on lower motor neurons and interneurons in the spinal cord, controlling movements of the limbs and trunk. There are more than one million neu ...
(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
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
Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pro ...
-
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.
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
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
s or disrupted
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
indicating that they were not formed through Wallerian degeneration.
Potential role in schizophrenia
Synaptic pruning has been suggested to have a role in the pathology of neurodevelopmental disorders such as
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
, as well as in
autism spectrum disorder
Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
. ''
''
Microglia
Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
have been implicated in synaptic pruning, as they have roles in both the immune response as
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s as well as in neuronal upkeep and
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
in the CNS during fetal development, early postnatal development, and adolescence, in which they engulf unneeded or redundant synapses via
phagocytosis
Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...
. ''
'' 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)
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.
Genes in the
Complement Component 4
Complement component 4 (C4), in humans, is a protein involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity with ...
(C4) locus of the
major histocompatibility complex
The major histocompatibility complex (MHC) is a large Locus (genetics), locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for Cell (biology), cell surface proteins essential for the adaptive immune system. The ...
(MHC), which encode for
complement factors, have also been tied to schizophrenia risk through
gene linkage studies.
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.
Specifically, complement factors C1q and C3 have been found to have a role in microglia-mediated synaptic pruning. ''
'' Carriers of C4 risk variants have also been found to be tied to this kind of synapse overpruning in microglia.
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.
See also
*
Neuroplasticity
Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...
References
{{reflist
Developmental neuroscience