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Perineuronal nets (PNNs) are specialized
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
structures responsible for
synaptic stabilization
Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased ex ...
in the adult brain.
PNNs are found around certain
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
cell bodies and proximal
neurites
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, ...
in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. PNNs play a critical role in the closure of the childhood
critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
, and their digestion can cause restored critical period-like
synaptic plasticity in the adult brain. They are largely negatively charged and composed of
chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles ...
s, 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
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
,
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
,
brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...
, and the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
. 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 interneuron
Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. ...
s and are thought to be responsible for maintaining the
excitatory/
inhibitory balance in the adult brain.
History
The existence of PNNs has been inferred by
Golgi, 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
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, hor ...
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
chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles ...
s (CSPGs). However, the authors clung to the idea that the material was intricately connected to the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...
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 proteoglycan
Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles ...
s, molecules that consist of a core protein and a
glycosaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
(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
Brevican core protein is a protein that in humans is encoded by the ''BCAN'' gene. Brevican is a member of the lectican protein family.
Brevican is localised to the surface of neurons in the brain. In melanocytic cells, BCAN gene expression ...
,
neurocan
Neurocan core protein is a protein that in humans is encoded by the ''NCAN'' gene.
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thou ...
,
versican,
aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican (chondroitin sulfate pr ...
,
phosphacan,
hyaluronan
Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglyca ...
,
tenascin-R and various link proteins. The CSPGs aggrecan, versican, neurocan, brevican, and phosphacan are bound to hyaluronan. Many of the components of PNNs are also expressed other forms of ECM in the brain. Aggrecan is selectively expressed in PNNs and is essential for the construction and maintenance of PNNs. 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,
thus it is not selective to PNNs. Mutant mice deficient in tenascin-R or link protein have attenuated PNNs,
In the cortex and other subcortical areas, PNNs preferentially surround
GABAergic
In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...
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 GABA
A 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
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
.
Functions
Neuroprotection
A fine regulation of
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
al and
dendritic
Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to:
Biology
*Dendrite, a branched projection of a neuron
* Dendrite (non-neuronal), branching projections of certain skin cells and immune cells
Physical
*Dendr ...
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
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can ...
-associated proteins and CSPGs. In order to assess the physiological role of PNNs in the undamaged CNS, ChABC was injected in the healthy
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
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.
Restriction of AMPA receptor mobility
Cell surface proteins, including
neurotransmitter receptor
A neurotransmitter receptor (also known as a neuroreceptor) is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which ther ...
s, are highly mobile in the
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
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 potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
, a short duration of both
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
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.
Role in neuroplasticity
PNNs play an important role in
neuroplasticity
Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it p ...
. 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
Brevican core protein is a protein that in humans is encoded by the ''BCAN'' gene. Brevican is a member of the lectican protein family.
Brevican is localised to the surface of neurons in the brain. In melanocytic cells, BCAN gene expression ...
,
versican,
neurocan
Neurocan core protein is a protein that in humans is encoded by the ''NCAN'' gene.
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thou ...
, and
NG2) increases after injury. ''In vivo'' treatment with ChABC results in the enhancement of the regeneration of axons (specifically
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
rgic 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.
Ocular dominance plasticity
The
critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
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
The visual system comprises the sensory organ (the eye) and parts of the central nervous system (the retina containing photoreceptor cells, the optic nerve, the optic tract and the visual cortex) which gives organisms the sense of sight (th ...
. Normally, the primary visual cortex contains neurons organized in
ocular dominance column Ocular dominance columns are stripes of neurons in the visual cortex of certain mammals (including humans) that respond preferentially to input from one eye or the other. The columns span multiple cortical layers, and are laid out in a striped patt ...
s, with groups of neurons responding preferentially to one eye or the other. If an animal's dominant eye is sutured early in life and kept sutured through the visual critical period (
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 (4–5 weeks-old in mice (Gordon ...
), the
cortex
Cortex or cortical may refer to:
Biology
* Cortex (anatomy), the outermost layer of an organ
** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain''
*** Motor cortex, the regions of the cerebral cortex i ...
permanently responds preferentially to the eye that was kept open, resulting in
ocular dominance
Ocular dominance, sometimes called eye preference or eyedness, is the tendency to prefer visual perception, visual input from one eye to the other. It is somewhat analogous to the laterality of right- or left-handedness; however, the side of the d ...
shift. However, if the eye is sutured after the critical period, the shift 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 ocular dominance shift 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 deprived since youth, digestion of PNNs brought about a full structural and functional recovery (recovery of ocular dominance, visual acuity, and
dendritic spine
A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical si ...
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 conditioning
Pavlovian 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 (e.g. an electrical shock) is associated with a particular neutral context (e.g., a r ...
in animals is used to model anxiety disorders such as
PTSD
Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a ...
. Fear conditioning works by pairing an initially
neutral stimulus
A neutral stimulus is a stimulus (physiology), 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 condi ...
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 is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...
. 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
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
coincides with this switch in fear memory resilience. In the adult animal, degradation of PNNs in the
amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
with ChABC renders subsequently 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
Bird vocalization includes both bird calls and bird songs. In non-technical use, bird songs are the bird sounds that are melodious to the human ear. In ornithology and birding, songs (relatively complex vocalizations) are distinguished by func ...
learning in the
zebra finch
The zebra finches are two species of estrildid finch in the genus ''Taeniopygia'' found in Australia and Indonesia. They are seed-eaters that travel in large flocks.
The species are:
Previously, both species were classified as a single species ...
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
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
. Reopening of the critical period in zebra finches may lead to discoveries leading to treatment for these disorders.
Role in CNS pathology
Epilepsy
Epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
is a chronic neurological disorder characterized by abnormal electrical activity in the brain. This abnormal electrical activity results in increased
plastic
Plastics are a wide range of synthetic or semi-synthetic materials that use polymers as a main ingredient. Their plasticity makes it possible for plastics to be moulded, extruded or pressed into solid objects of various shapes. This adaptab ...
changes that play a part of the
pathogenesis
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
of the disease.
Following seizures, there is a decrease in phosphacan and phosphacan-positive PNNs and an increase in cleaved
brevican
Brevican core protein is a protein that in humans is encoded by the ''BCAN'' gene. Brevican is a member of the lectican protein family.
Brevican is localised to the surface of neurons in the brain. In melanocytic cells, BCAN gene expression ...
in the
temporal lobe
The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain.
The temporal lobe ...
and
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
. Seizures also increase the amount of full-length
neurocan
Neurocan core protein is a protein that in humans is encoded by the ''NCAN'' gene.
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thou ...
, 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.
Stroke
Following
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, 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 (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican (chondroitin sulfate pr ...
,
versican, and phosphacan and an accumulation of full-length
neurocan
Neurocan core protein is a protein that in humans is encoded by the ''NCAN'' gene.
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thou ...
. This downregulation of PNNs also occurs in brain regions as distant as the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
. 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 disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. PNNs may provide protection against
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
,
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, and the formation of
neurofibrillary tangles
Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
.
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.
[{{cite journal , last1 = Brückner , first1 = G. , last2 = Hausen , first2 = D. , last3 = Härtig , first3 = W. , last4 = Drlicek , first4 = M. , last5 = Arendt , first5 = T. , last6 = Brauer , first6 = K. , year = 1999 , title = Cortical areas abundant in extracellular matrix chondroitin sulphate proteoglycans are less affected by cytoskeletal changes in Alzheimer's disease , journal = Neuroscience , volume = 92 , issue = 3, pages = 791–805 , doi=10.1016/s0306-4522(99)00071-8, pmid = 10426522 , s2cid = 24281926 ] 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
Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...
and
neurofibrillary tangles
Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
. 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
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labio ...
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 matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
*
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles i ...
s
*
Critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
*
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
References
Neuroplasticity