Perineuronal net
Encyclopedia
Perineuronal nets are specialized extracellular matrix
structures responsible for synaptic
stabilization in the adult brain. These PNNs are found around certain neuron
cell bodies and proximal neurites in the central nervous system
. PNNs play a critical role in the closure of critical periods and their digestion allows the reopening of these critical periods in the adult brain. They are largely negatively charged and composed of chondroitin sulfate proteoglycans
, molecules that play a key role in development and plasticity
during postnatal development and in the adult.
PNNs appear to be mainly present in the cortex
, hippocampus
, thalamus
, brainstem, and the spinal cord
. Studies of the rat brain have shown that the cortex contains high numbers of PNNs in the motor
and primary sensory areas and relatively fewer in the association and limbic cortices. In the cortex, PNNs are associated mostly with inhibitory
interneurons
and are thought to be responsible for maintaining the excitatory
/inhibitory
balance in the adult brain.
, Lugaro, Donaggio, Martinotti, Ramón y Cajal and Meyer. However, Ramón y Cajal credits Golgi with the discovery of PNNs because he was the first to draw attention to them and gave the first precise description in 1893. Moreover, Golgi brought interest to the subject due to his opinion that the PNN was not a neuronal structure but rather a "kind of corset of neurokeratin which impeded the spread of current from cell to cell". Despite debating the topic, Ramón y Cajal claimed that the perineuronal net was simply a staining artifact derived from the coagulation of extracellular fluids. Due to his influential opinion at the time, interest in the topic subsided.
Interest arose in the 1960s when several authors drew attention to the presence of periodic-acid-Schiff-positive (PAS-positive) material surrounding nerve cells. This PAS-positive material was suspected of being composed of negatively charged substances, such as CSPGs. However, the authors clung to the idea that the material was intricately connected to the blood-brain barrier
and failed to see the similarities it had with the perineuronal net described by Golgi. Interest only rose again in the past few decades when it was discovered that PNNs constitute markers for physiologically mature neurons.
, molecules that consist of a core protein and a glycosaminoglycan
(GAG) chain. The CS-GAG chains associated with PNNs differs from those found floating in the extra-cellular matrix in a noncondensed form. PNNs are composed of brevican, neurocan, versican
, aggrecan
, phosphacan, hyaluronan
, tenascin-R
and various link proteins. The CSPGs aggrecan, versican, neurocan, breican, and phosphacan are bound to hyaluronan. PNNs found in both the brain and the spinal cord have the same composition. Chondroitinase ABC (ChABC), a bacterial enzyme routinely used to digest CSPGs, works by catalyzing the removal of the CS-GAG chains of CSPGs.
In the cortex and other subcortical areas, PNNs preferentially surround GABAergic interneurons containing the calcium-binding protein parvalbumin
. The onset of the critical period corresponds closely to the emergence of parvalbumin-positive cells. Parvalbumin-positive cells synapse onto α1-subunit-containing GABAA receptors
. The α1-subunit-containing GABAA receptors have been shown to be the only GABAA receptors that drive cortical plasticity. For this reason, PNNs were first thought to have a strong role in the closure of the critical period
.
and dendritic
growth is required in the adult CNS to preserve important connections while still allowing for structural plasticity
. This function has been recognized to be mediated by several myelin
-associated proteins and CSPGs. In order to assess the physiological role of PNNs in the undamaged CNS, ChABC was injected in the healthy cerebellum
of adult rats. In the site of ChABC injections, there was profuse outgrowth of the terminal branches of Purkinje cell
neurons. However, myelinated axon segments were not affected and remained normal. Purkinje axon sprouting was first evident four days after the degradation of CSPGs. Within 42 days, the expression of CSPGs gradually recovered, at which point axon outgrowth regressed, indicating that there was no significant formation of stable synaptic contacts. While CSPGs are very important in neuroprotection, this indicates that CSPGs may not be the only molecules important for the preservation of anatomical plasticity.
, are highly mobile in the plasma membrane due to lateral diffusion. Fast movements of AMPA-type glutamate receptors (AMPARs) are involved in the modulation of synaptic transmission. As a receptor is used, it becomes desensitized and unable to operate efficiently for a short period of time. Diffusion of the desensitized receptor for the exchange of a naive functional one increases synaptic fidelity during fast repetitive stimulation. PNNs' compartmentalize the neuronal surface and act as lateral diffusion barriers for AMPARs, limiting synaptic exchange. This may be part of the reason that synaptic plasticity is limited once PNNs become upregulated.
, a short duration of both action potentials and the refractory period, a high firing frequency, and an almost constant amplitude of their action potentials. It appears that both Kv3.1 channels and PNNs are both required for the fast-spiking behavior of these neurons. These potassium channels are important because outward potassium currents are responsible for the repolarization of the cell membrane during an action potential. It has been shown that Kv3.1 currents allow a neuron to follow a high frequency stimulation and/or to generate high firing rates without spike adaption, characteristics that fit well with fast-spiking cells. This characteristic of the cells is important as blockade of the Kv3.1b channel has been shown to slow the rate of ocular dominance plasticity.
PNNs, with their strongly negative charge, may serve as cation exchangers preventing the free diffusion of potassium or sodium ions. Due to the spatial, temporal, and numerical disproportions between Na+ influx and K+ efflux, the PNN provides a possible buffering
system for extracellular cations. However, this hypothesis has yet to be proven.
. Traumatic injury of the CNS results in degeneration of denervated and damaged neurons, the formation of a glial scar
, and collateral sprouting of surviving neurons. PNNs have been shown to be inhibitory to axonal regeneration and outgrowth. CSPGs
are the main axon growth inhibitory molecules in the glial scar that play a role in the failure of the axon to regenerate after injury. In the rat brain and spinal cord, the expression of various CSPGs (brevican, versican
, neurocan, and NG2) increases after injury. In vivo treatment with ChABC results in the enhancement of the regeneration of axons (specifically domaminergic
neurons) and the promotion of axon regeneration and functional recovery following spinal cord injury.
CSPGs
and PNNs are also implicated in the restricted plasticity present after CNS injury. In the rat cerebellum, application of ChABC promotes structural plasticity of Purkinje axons. Following spinal cord injury, rats treated with ChABC show structural and functional recovery in the form of increased regrowth of axons into the denervated territory and the recovery of motor and bladder function. Plasticity of intact areas in the brain stem and spinal cord also increases following spinal cord injury.
is a stage when a necessary amount of experience is required for the proper organization of a neural pathway. The absence of this experience may lead to the permanent formation of incorrect connections. The classic model of the critical period has been the visual system
. Normally, the primary visual cortex contains neurons organized in ocular dominance column, with groups of neurons responding preferentially to one eye or the other. If an animal's eye is sutured early in life and kept sutured through the visual critical period, the cortex
permanently responds preferentially to the eye that was kept open, resulting in monocular deprivation
. However, if the eye is sutured after the critical period, monocular deprivation does not occur.
In rats, digestion of PNNs using the bacterial enzyme chondroitinase ABC reactivates the visual critical period. Specifically, digestion of PNNs in the visual cortex well after the closure of the critical period (postnatal day 70) reactivated critical period plasticity and allowed monocular deprivation to occur. However, the effects of monocular deprivation in the reactivated case were not as strong as monocular deprivation during a normal critical period. Additionally, in adult rats that had been monocularly deprivated since youth, digestion of PNNs brought about a full structural and functional recovery (recovery of ocular dominance, visual acuity, and dendritic spine
density). However, this recovery only occurred once the open eye was sutured to allow the cortical representation of the deprived eye to recover.
in animals is used to model anxiety disorders such as PTSD. Fear conditioning works by pairing an initially neutral stimulus
with an aversive stimulus, leading to long-lasting fear memories. In an adult animal, fear conditioning induces a permanent memory resilient to erasure by extinction
. After extinction, conditioned fear responses can recover spontaneously after a reexposure to the aversive stimulus. In contrast, in early postnatal development, extinction of a conditioned fear response leads to memory erasure. The organization of PNNs in the amygdala
coincides with this switch in fear memory resilience. In the adult animal, degradation of PNNs in the amygdala
with ChABC renders subsequentially acquired fear memories susceptible to erasure. Extinction training was necessary for the loss of fear behavior. Additionally, fear memories acquired before the degradation of the PNNs were not affected by their degradation.
occurs during a critical period similar to that for human speech. This critical period occurs in two parts. The first consists of an early perceptual phase in which sounds are merely memorized. This is followed by a second sensorimotor phase in which feedback is used to shape proper sounds. In the song nuclei HVC, over 80% of PNNs surround parvalbumin
-positive neurons. The presence of perineuronal nets predicts the maturity of a zebra finch's song, with greater PNN density indicating a more mature song and likely greater synaptic stability. Unlike the visual critical period, extensive preliminary investigation has shown that degrading the PNNs with ChABC does not reopen the critical period of sensorimotor plasticity. This can be attributed to the additional complicating factors present in a sensorimotor system compared to a purely sensory system. In humans, complications in the speech sensorimotor critical period is implicated in disorders such as autism
. Reopening of the critical period in zebra finches may lead to discoveries leading to treatment for these disorders.
is a chronic neurological disorder characterized by abnormal electrical activity in the brain. This abnormal electrical activity results in increased plastic
changes that play a part of the pathogenesis
of the disease. Following seizures, there is a decrease in phosphacan and phosphacan-positive PNNs and an increase in cleaved brevican in the temporal lobe
and hippocampus
. Seizures also increase the amount of full-length neurocan, a CSPG
only found in the neonatal brain. This degradation of CSPGs and PNNs could be responsible for the increased plasticity associated with the disorder.
, there is some increased plasticity resulting in the restoration of some function. In the rat model, following a cortical lesion, there is a reduction of PNNs in the region surrounding the infarction. Specifically, there is a reduction in the CSPGs aggrecan
, versican
, and phosphacan and an accumulation of full-length neurocan. This downregulation of PNNs also occurs in brain regions as distant as the thalamus
. The degradation of PNNs may be responsible for the increased plasticity seen post-stroke. One issue with typical stroke recovery is the typical period of increased plasticity is generally not long enough to allow stroke patients acceptable recovery of function. One possible treatment strategy may be to degrade PNNs for a longer period of time to allow for greater recovery.
. PNNs may provide protection against excitotoxicity
, oxidative stress
, and the formation of neurofibrillary tangles. There have been conflicting reports as to the number of PNNs in the human Alzheimer's brain, with some studies reporting a reduction and others reporting no change. There is no clear consensus as the susceptibility of parvalbumin
-positive neurons, the majority of neurons surrounded by PNNs. However, PNNs have been found to localize with both amyloid plaques and neurofibrillary tangles. Since amyloid plaques have been implicated in the progression of Alzheimer's disease, this suggests that PNNs are either instrumental in their formation or are a reaction to their formation. In vitro studies have shown that CSPGs promote beta amyloid fibril formation. Since beta amyloid is a strong stimulant to CSPG production and CSPGs are inhibitory to neuronal growth and synaptic plasticity, this may lead to the decreased axon density and synaptic loss in Alzheimer's disease.
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
structures responsible for synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
stabilization in the adult brain. These PNNs are found around certain neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
cell bodies and proximal neurites in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. PNNs play a critical role in the closure of critical periods and their digestion allows the reopening of these critical periods in the adult brain. They are largely negatively charged and composed of chondroitin sulfate proteoglycans
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
, molecules that play a key role in development and plasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
during postnatal development and in the adult.
PNNs appear to be mainly present in the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, brainstem, and the 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...
. Studies of the rat brain have shown that the cortex contains high numbers of PNNs in the motor
Motor cortex
Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...
and primary sensory areas and relatively fewer in the association and limbic cortices. In the cortex, PNNs are associated mostly with inhibitory
Inhibitory postsynaptic potential
An inhibitory postsynaptic potential is a synaptic potential that decreases the chance that a future action potential will occur in a postsynaptic neuron or α-motoneuron...
interneurons
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
and are thought to be responsible for maintaining the excitatory
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
/inhibitory
Inhibitory postsynaptic potential
An inhibitory postsynaptic potential is a synaptic potential that decreases the chance that a future action potential will occur in a postsynaptic neuron or α-motoneuron...
balance in the adult brain.
History
The existence of PNNs has been implicated by GolgiCamillo Golgi
Camillo Golgi was an Italian physician, pathologist, scientist, and Nobel laureate.-Biography:Camillo Golgi was born in the village of Corteno, Lombardy, then part of the Austrian Empire. The village is now named Corteno Golgi in his honour. His father was a physician and district medical officer...
, Lugaro, Donaggio, Martinotti, Ramón y Cajal and Meyer. However, Ramón y Cajal credits Golgi with the discovery of PNNs because he was the first to draw attention to them and gave the first precise description in 1893. Moreover, Golgi brought interest to the subject due to his opinion that the PNN was not a neuronal structure but rather a "kind of corset of neurokeratin which impeded the spread of current from cell to cell". Despite debating the topic, Ramón y Cajal claimed that the perineuronal net was simply a staining artifact derived from the coagulation of extracellular fluids. Due to his influential opinion at the time, interest in the topic subsided.
Interest arose in the 1960s when several authors drew attention to the presence of periodic-acid-Schiff-positive (PAS-positive) material surrounding nerve cells. This PAS-positive material was suspected of being composed of negatively charged substances, such as CSPGs. However, the authors clung to the idea that the material was intricately connected to the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and failed to see the similarities it had with the perineuronal net described by Golgi. Interest only rose again in the past few decades when it was discovered that PNNs constitute markers for physiologically mature neurons.
Composition
PNNs are composed of a condensed matrix of chondroitin sulfate proteoglycansChondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
, molecules that consist of a core protein and a glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
(GAG) chain. The CS-GAG chains associated with PNNs differs from those found floating in the extra-cellular matrix in a noncondensed form. PNNs are composed of brevican, neurocan, versican
Versican
Versican, also known as VCAN, is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene....
, aggrecan
Aggrecan
Aggrecan also known as cartilage-specific proteoglycan core protein or chondroitin sulfate proteoglycan 1 is a protein that in humans is encoded by the ACAN gene. This gene is a member of the aggrecan/versican proteoglycan family...
, phosphacan, hyaluronan
Hyaluronan
Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues...
, tenascin-R
Tenascin-R
Tenascin-R is a protein that in humans is encoded by the TNR gene.- Function :Tenascin-R is an extracellular matrix protein expressed primarily in the central nervous system. It is a member of the tenascin gene family, which includes at least 3 genes in mammals: TNC , TNX , and TNR...
and various link proteins. The CSPGs aggrecan, versican, neurocan, breican, and phosphacan are bound to hyaluronan. PNNs found in both the brain and the spinal cord have the same composition. Chondroitinase ABC (ChABC), a bacterial enzyme routinely used to digest CSPGs, works by catalyzing the removal of the CS-GAG chains of CSPGs.
In the cortex and other subcortical areas, PNNs preferentially surround GABAergic interneurons containing the calcium-binding protein parvalbumin
Parvalbumin
Parvalbumin is a calcium-binding albumin protein with low molecular weight .It has three EF hand motifs and is structurally related to calmodulin and troponin C...
. The onset of the critical period corresponds closely to the emergence of parvalbumin-positive cells. Parvalbumin-positive cells synapse onto α1-subunit-containing GABAA receptors
GABRA1
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
. The α1-subunit-containing GABAA receptors have been shown to be the only GABAA receptors that drive cortical plasticity. For this reason, PNNs were first thought to have a strong role in the closure of the critical period
Critical period
This article is about a critical period in an organism's or person's development. See also America's Critical Period.In general, a critical period is a limited time in which an event can occur, usually to result in some kind of transformation...
.
Neuroprotection
A fine regulation of axonalAxon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
and dendritic
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
growth is required in the adult CNS to preserve important connections while still allowing for structural plasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
. This function has been recognized to be mediated by several myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
-associated proteins and CSPGs. In order to assess the physiological role of PNNs in the undamaged CNS, ChABC was injected in the healthy cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
of adult rats. In the site of ChABC injections, there was profuse outgrowth of the terminal branches of Purkinje cell
Purkinje
Purkinje is a name attributed to several biological features, so named for their discovery by Czech anatomist Jan Evangelista Purkyně:*Purkinje cells, located in the cerebellum*Purkinje fibers, located in the heart*The visual Purkinje effect...
neurons. However, myelinated axon segments were not affected and remained normal. Purkinje axon sprouting was first evident four days after the degradation of CSPGs. Within 42 days, the expression of CSPGs gradually recovered, at which point axon outgrowth regressed, indicating that there was no significant formation of stable synaptic contacts. While CSPGs are very important in neuroprotection, this indicates that CSPGs may not be the only molecules important for the preservation of anatomical plasticity.
Restriction of AMPA Receptor Mobility
Cell surface proteins, including neurotransmitter receptorsNeurotransmitter receptor
A Neurotransmitter receptor is a membrane receptor protein that is activated by a Neurotransmitter. A membrane protein interacts with the lipid bilayer that encloses the cell and a membrane receptor protein interacts with a chemical in the cells external environment, which binds to the cell...
, are highly mobile in the plasma membrane due to lateral diffusion. Fast movements of AMPA-type glutamate receptors (AMPARs) are involved in the modulation of synaptic transmission. As a receptor is used, it becomes desensitized and unable to operate efficiently for a short period of time. Diffusion of the desensitized receptor for the exchange of a naive functional one increases synaptic fidelity during fast repetitive stimulation. PNNs' compartmentalize the neuronal surface and act as lateral diffusion barriers for AMPARs, limiting synaptic exchange. This may be part of the reason that synaptic plasticity is limited once PNNs become upregulated.
Buffering System for Cations
Most of the parvalbumin-positive neurons surrounded by PNNs also contain the potassium channel Kv3.1b subunit. These specific cells have been identified as fast-spiking cells. These neurons have a low input resistance of the cell membrane, a high resting membrane potentialMembrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
, a short duration of both action potentials and the refractory period, a high firing frequency, and an almost constant amplitude of their action potentials. It appears that both Kv3.1 channels and PNNs are both required for the fast-spiking behavior of these neurons. These potassium channels are important because outward potassium currents are responsible for the repolarization of the cell membrane during an action potential. It has been shown that Kv3.1 currents allow a neuron to follow a high frequency stimulation and/or to generate high firing rates without spike adaption, characteristics that fit well with fast-spiking cells. This characteristic of the cells is important as blockade of the Kv3.1b channel has been shown to slow the rate of ocular dominance plasticity.
PNNs, with their strongly negative charge, may serve as cation exchangers preventing the free diffusion of potassium or sodium ions. Due to the spatial, temporal, and numerical disproportions between Na+ influx and K+ efflux, the PNN provides a possible buffering
Buffering agent
A buffering agent is a weak acid or base used to maintain the acidity of a solution at a chosen value. The function of a buffering agent is to prevent a rapid change in pH when acids or bases are added to the solution. Buffering agents have variable properties—some are more soluble than others;...
system for extracellular cations. However, this hypothesis has yet to be proven.
Role in Neuroplasticity
PNNs play an important role in neuroplasticityNeuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
. Traumatic injury of the CNS results in degeneration of denervated and damaged neurons, the formation of a glial scar
Glial scar
Glial scar formation is a reactive cellular process involving astrogliosis that occurs after injury to the Central Nervous System. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system...
, and collateral sprouting of surviving neurons. PNNs have been shown to be inhibitory to axonal regeneration and outgrowth. CSPGs
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
are the main axon growth inhibitory molecules in the glial scar that play a role in the failure of the axon to regenerate after injury. In the rat brain and spinal cord, the expression of various CSPGs (brevican, versican
Versican
Versican, also known as VCAN, is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene....
, neurocan, and NG2) increases after injury. In vivo treatment with ChABC results in the enhancement of the regeneration of axons (specifically domaminergic
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
neurons) and the promotion of axon regeneration and functional recovery following spinal cord injury.
CSPGs
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
and PNNs are also implicated in the restricted plasticity present after CNS injury. In the rat cerebellum, application of ChABC promotes structural plasticity of Purkinje axons. Following spinal cord injury, rats treated with ChABC show structural and functional recovery in the form of increased regrowth of axons into the denervated territory and the recovery of motor and bladder function. Plasticity of intact areas in the brain stem and spinal cord also increases following spinal cord injury.
Ocular Dominance Plasticity
The critical periodCritical period
This article is about a critical period in an organism's or person's development. See also America's Critical Period.In general, a critical period is a limited time in which an event can occur, usually to result in some kind of transformation...
is a stage when a necessary amount of experience is required for the proper organization of a neural pathway. The absence of this experience may lead to the permanent formation of incorrect connections. The classic model of the critical period has been the visual system
Visual system
The visual system is the part of the central nervous system which enables organisms to process visual detail, as well as enabling several non-image forming photoresponse functions. It interprets information from visible light to build a representation of the surrounding world...
. Normally, the primary visual cortex contains neurons organized in ocular dominance column, with groups of neurons responding preferentially to one eye or the other. If an animal's eye is sutured early in life and kept sutured through the visual critical period, the cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
permanently responds preferentially to the eye that was kept open, resulting in monocular deprivation
Monocular deprivation
Monocular deprivation is an experimental technique used by neuroscientists to study central nervous system plasticity. Generally, one of an animal's eyes is sutured shut during a period of high cortical plasticity...
. However, if the eye is sutured after the critical period, monocular deprivation does not occur.
In rats, digestion of PNNs using the bacterial enzyme chondroitinase ABC reactivates the visual critical period. Specifically, digestion of PNNs in the visual cortex well after the closure of the critical period (postnatal day 70) reactivated critical period plasticity and allowed monocular deprivation to occur. However, the effects of monocular deprivation in the reactivated case were not as strong as monocular deprivation during a normal critical period. Additionally, in adult rats that had been monocularly deprivated since youth, digestion of PNNs brought about a full structural and functional recovery (recovery of ocular dominance, visual acuity, and dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
density). However, this recovery only occurred once the open eye was sutured to allow the cortical representation of the deprived eye to recover.
Fear Memories
Fear conditioningFear conditioning
Fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus , resulting in the expression of fear responses to the originally neutral...
in animals is used to model anxiety disorders such as PTSD. Fear conditioning works by pairing an initially neutral stimulus
Neutral stimulus
A neutral stimulus is a stimulus which initially produces no specific response other than focusing attention. In classical conditioning, when used together with an unconditioned stimulus, the neutral stimulus becomes a conditioned stimulus....
with an aversive stimulus, leading to long-lasting fear memories. In an adult animal, fear conditioning induces a permanent memory resilient to erasure by extinction
Extinction (psychology)
Extinction is the conditioning phenomenon in which a previously learned response to a cue is reduced when the cue is presented in the absence of the previously paired aversive or appetitive stimulus.-Fear conditioning:...
. After extinction, conditioned fear responses can recover spontaneously after a reexposure to the aversive stimulus. In contrast, in early postnatal development, extinction of a conditioned fear response leads to memory erasure. The organization of PNNs in the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
coincides with this switch in fear memory resilience. In the adult animal, degradation of PNNs in the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
with ChABC renders subsequentially acquired fear memories susceptible to erasure. Extinction training was necessary for the loss of fear behavior. Additionally, fear memories acquired before the degradation of the PNNs were not affected by their degradation.
Developmental Song Learning
Developmental song learning is a model used for the sensorimotor critical period. Birdsong learning in the zebra finchZebra Finch
The Zebra Finch, Taeniopygia guttata, is the most common and familiar estrildid finch of Central Australia and ranges over most of the continent, avoiding only the cool moist south and the tropical far north. It also can be found natively in Indonesia and East Timor...
occurs during a critical period similar to that for human speech. This critical period occurs in two parts. The first consists of an early perceptual phase in which sounds are merely memorized. This is followed by a second sensorimotor phase in which feedback is used to shape proper sounds. In the song nuclei HVC, over 80% of PNNs surround parvalbumin
Parvalbumin
Parvalbumin is a calcium-binding albumin protein with low molecular weight .It has three EF hand motifs and is structurally related to calmodulin and troponin C...
-positive neurons. The presence of perineuronal nets predicts the maturity of a zebra finch's song, with greater PNN density indicating a more mature song and likely greater synaptic stability. Unlike the visual critical period, extensive preliminary investigation has shown that degrading the PNNs with ChABC does not reopen the critical period of sensorimotor plasticity. This can be attributed to the additional complicating factors present in a sensorimotor system compared to a purely sensory system. In humans, complications in the speech sensorimotor critical period is implicated in disorders such as autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
. Reopening of the critical period in zebra finches may lead to discoveries leading to treatment for these disorders.
Epilepsy
EpilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
is a chronic neurological disorder characterized by abnormal electrical activity in the brain. This abnormal electrical activity results in increased plastic
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
changes that play a part of the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of the disease. Following seizures, there is a decrease in phosphacan and phosphacan-positive PNNs and an increase in cleaved brevican in the temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....
and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. Seizures also increase the amount of full-length neurocan, a CSPG
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
only found in the neonatal brain. This degradation of CSPGs and PNNs could be responsible for the increased plasticity associated with the disorder.
Stroke
Following strokeStroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, there is some increased plasticity resulting in the restoration of some function. In the rat model, following a cortical lesion, there is a reduction of PNNs in the region surrounding the infarction. Specifically, there is a reduction in the CSPGs aggrecan
Aggrecan
Aggrecan also known as cartilage-specific proteoglycan core protein or chondroitin sulfate proteoglycan 1 is a protein that in humans is encoded by the ACAN gene. This gene is a member of the aggrecan/versican proteoglycan family...
, versican
Versican
Versican, also known as VCAN, is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene....
, and phosphacan and an accumulation of full-length neurocan. This downregulation of PNNs also occurs in brain regions as distant as the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
. The degradation of PNNs may be responsible for the increased plasticity seen post-stroke. One issue with typical stroke recovery is the typical period of increased plasticity is generally not long enough to allow stroke patients acceptable recovery of function. One possible treatment strategy may be to degrade PNNs for a longer period of time to allow for greater recovery.
Alzheimer's Disease
There appear to be several roles for CSPGs in Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. PNNs may provide protection against excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, and the formation of neurofibrillary tangles. There have been conflicting reports as to the number of PNNs in the human Alzheimer's brain, with some studies reporting a reduction and others reporting no change. There is no clear consensus as the susceptibility of parvalbumin
Parvalbumin
Parvalbumin is a calcium-binding albumin protein with low molecular weight .It has three EF hand motifs and is structurally related to calmodulin and troponin C...
-positive neurons, the majority of neurons surrounded by PNNs. However, PNNs have been found to localize with both amyloid plaques and neurofibrillary tangles. Since amyloid plaques have been implicated in the progression of Alzheimer's disease, this suggests that PNNs are either instrumental in their formation or are a reaction to their formation. In vitro studies have shown that CSPGs promote beta amyloid fibril formation. Since beta amyloid is a strong stimulant to CSPG production and CSPGs are inhibitory to neuronal growth and synaptic plasticity, this may lead to the decreased axon density and synaptic loss in Alzheimer's disease.
See also
- Extracellular matrixExtracellular matrixIn biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
- Chondroitin sulfate proteoglycansChondroitin sulfate proteoglycanChondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
- Critical periodCritical periodThis article is about a critical period in an organism's or person's development. See also America's Critical Period.In general, a critical period is a limited time in which an event can occur, usually to result in some kind of transformation...
- Synaptic plasticitySynaptic plasticityIn neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...