Brain-derived neurotrophic factor (BDNF), or abrineurin, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
[ found in the and the periphery.] that, in humans, is encoded by the ''BDNF''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
BDNF is a member of the
neurotrophin family of growth factors, which are related to the canonical
nerve growth factor (NGF), a family which also includes
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activ ...
and
NT-4
Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the ''NTF4'' gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase
Receptor tyrosine kinase ...
/NT-5.
Neurotrophic factors
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...
are found in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
BDNF activates the
TrkB
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...
tyrosine kinase receptor
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...
.
Function
BDNF acts on 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. ...
s of 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 ...
and the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
expressing
TrkB
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...
, helping to support survival of existing neurons, and encouraging growth and
differentiation of new neurons and
synapses.
In the brain it is active in the
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 system, ...
,
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 ...
, and
basal forebrain
Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal b ...
—areas vital to
learning,
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
, and higher thinking.
BDNF is also expressed in the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
,
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s,
prostate
The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...
,
motor neurons, and
skeletal muscle, and is also found in
saliva.
BDNF itself is important for
long-term memory
Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long- ...
.
Although the vast majority of neurons in the
mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural
stem cells in a process known as
neurogenesis. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active.
Mice born without the ability to make BDNF have developmental defects in the brain and
sensory nervous system
The sensory nervous system is a part of the nervous system responsible for processing sensory information. A sensory system consists of sensory neurons (including the sensory receptor cells), neural pathways, and parts of the brain involved i ...
, and usually die soon after birth, suggesting that BDNF plays an important role in normal
neural development.
Other important neurotrophins structurally related to BDNF include
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activ ...
,
NT-4
Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the ''NTF4'' gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase
Receptor tyrosine kinase ...
, and
NGF.
BDNF is made in the
endoplasmic reticulum and secreted from
dense-core vesicle
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s. It binds
carboxypeptidase E
Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the ''CPE'' gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.
...
(CPE), and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense-core vesicles. The
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
for BDNF
knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons.
Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function.
Niacin
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...
appears to upregulate BDNF and
tropomyosin receptor kinase B
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recep ...
(TrkB) expression as well.
Mechanism of action
BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor,
TrkB
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...
(pronounced "Track B") and the
LNGFR
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic fact ...
(for ''low-affinity nerve growth factor receptor'', also known as p75).
It may also modulate the activity of various neurotransmitter receptors, including the
Alpha-7 nicotinic receptor
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits.Pharmacology, (Rang, Dale, Ritter & Moore, , 5th ed., Churchill Liv ...
.
BDNF has also been shown to interact with the
reelin
Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this impor ...
signaling chain.
[; see the chapter "A Tale of Two Genes: Reelin and BDNF"; pp. 237–45] The expression of reelin by
Cajal–Retzius cell
Cajal–Retzius cells (CR cells) (also known as Horizontal cells of Cajal) are a heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developmental cerebral cortex an ...
s goes down during development under the influence of BDNF.
The latter also decreases reelin expression in neuronal culture.
TrkB
The TrkB receptor is encoded by the
NTRK2 gene and is member of a receptor family of tyrosine kinases that includes
TrkA
Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the ''NTRK1'' gen ...
and
TrkC
Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene.
TrkC is the high affinity catalyt ...
. TrkB
autophosphorylation
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threoni ...
is dependent upon its ligand-specific association with BDNF, a widely expressed activity-dependent neurotrophic factor that regulates
plasticity and is dysregulated following
hypoxic
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the t ...
injury. The activation of the BDNF-TrkB pathway is important in the development of short-term memory and the growth of neurons.
LNGFR
The role of the other BDNF receptor,
p75, is less clear. While the TrkB receptor interacts with BDNF in a ligand-specific manner, all neurotrophins can interact with the p75 receptor.
When the p75 receptor is activated, it leads to activation of
NFkB receptor.
Thus, neurotrophic signaling may trigger
apoptosis rather than survival pathways in cells expressing the p75 receptor in the absence of Trk receptors. Recent studies have revealed a truncated isoform of the TrkB receptor (t-TrkB) may act as a dominant negative to the p75 neurotrophin receptor, inhibiting the activity of p75, and preventing BDNF-mediated cell death.
Expression
The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11.
Structurally, BDNF transcription is controlled by 8 different promoters, each leading to different transcripts containing one of 8 untranslated 5' exons (I to VIII) spliced to the 3' encoding
exon. Promoter IV activity, leading to the translation of exon IV-containing mRNA, is strongly stimulated by calcium and is primarily under the control of a
Cre regulatory component, suggesting a putative role for the transcription factor
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...
and the source of BDNF's activity-dependent effects .
There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression.
Stimulus-mediated neuronal excitation can lead to
NMDA receptor activation, triggering a calcium influx. Through a protein signaling cascade requiring
Erk,
CaM KII/IV,
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, and
PLC, NMDA receptor activation is capable of triggering BDNF exon IV transcription. BDNF exon IV expression also seems capable of further stimulating its own expression through TrkB activation. BDNF is released from the post-synaptic membrane in an activity-dependent manner, allowing it to act on local TrkB receptors and mediate effects that can leading to signaling cascades also involving Erk and CaM KII/IV.
Both of these pathways probably involve calcium-mediated phosphorylation of CREB at Ser133, thus allowing it to interact with BDNF's Cre regulatory domain and upregulate transcription.
However, NMDA-mediated receptor signaling is probably necessary to trigger the upregulation of BDNF exon IV expression because normally CREB interaction with CRE and the subsequent translation of the BDNF transcript is blocked by of the
basic helix-loop-helix
BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...
transcription factor protein 2 (
BHLHB2).
NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx.
Activation of
Dopamine receptor D5 also promotes expression of BDNF in
prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...
neurons.
Common SNPs in BDNF gene
BDNF has several known
single nucleotide polymorphisms (SNP), including, but not limited to, rs6265, C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442. As of 2008,
rs6265
Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for brain-derived neurotrophic factor.
Well over a hundred research studies have examined the polymorphism.
Associati ...
is the most investigated
SNP of the ''BDNF'' gene
Val66Met
A common
SNP in the BDNF gene is rs6265.
This point mutation in the coding sequence, a guanine to adenine switch at position 196, results in an amino acid switch: valine to methionine exchange at codon 66, Val66Met, which is in the prodomain of BDNF.
Val66Met is unique to humans.
The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation.[ The proteins resulting from mRNA that does get translated, are not trafficked and secreted normally, as the amino acid change occurs on the portion of the prodomain where sortilin binds; and sortilin is essential for normal trafficking.]
The Val66Met mutation results in a reduction of hippocampal tissue and has since been reported in a high number of individuals with learning and memory disorders, anxiety disorders, major depression
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
, and neurodegenerative diseases such as Alzheimer's and Parkinson's
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.
Role in synaptic transmission
Glutamatergic signaling
Glutamate is the brain's major excitatory neurotransmitter and its release can trigger the depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
of postsynaptic
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
neurons. AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
and NMDA
''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...
receptors are two ionotropic
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
glutamate receptors involved in glutamatergic neurotransmission
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
and essential to learning and memory via long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
. While AMPA receptor activation leads to depolarization via sodium influx, NMDA receptor activation by rapid successive firing allows calcium influx in addition to sodium. The calcium influx triggered through NMDA receptors can lead to expression of BDNF, as well as other genes thought to be involved in LTP, dendritogenesis, and synaptic stabilization.
NMDA receptor activity
NMDA receptor activation is essential to producing the activity-dependent molecular changes involved in the formation of new memories. Following exposure to an enriched environment, BDNF and NR1 phosphorylation levels are upregulated simultaneously, probably because BDNF is capable of phosphorylating NR1 subunits, in addition to its many other effects. One of the primary ways BDNF can modulate NMDA receptor activity is through phosphorylation and activation of the NMDA receptor one subunit, particularly at the PKC Ser-897 site. The mechanism underlying this activity is dependent upon both ERK and PKC signaling pathways, each acting individually, and all NR1 phosphorylation activity is lost if the TrKB receptor is blocked. PI3 kinase and Akt are also essential in BDNF-induced potentiation of NMDA receptor function and inhibition of either molecule eliminated receptor acBDNF can also increase NMDA receptor activity through phosphorylation of the NR2B
Glutamate MDAreceptor subunit epsilon-2, also known as ''N''-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the ''GRIN2B'' gene.
NMDA receptors
''N''-methyl-D-aspartate (NMDA) receptors are ...
subunit. BDNF signaling leads to the autophosphorylation of the intracellular domain of the TrkB receptor (ICD-TrkB). Upon autophosphorylation, Fyn
Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
associates with the pICD-TrkB through its Src homology domain 2 (SH2) and is phosphorylated at its Y416 site. Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site. Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus. Thus, BDNF can increase NMDA receptor activity through Fyn activation. This has been shown to be important for processes such as spatial memory in the hippocampus, demonstrating the therapeutic and functional relevance of BDNF-mediated NMDA receptor activation.
Synapse stability
In addition to mediating transient effects on NMDAR activation to promote memory-related molecular changes, BDNF should also initiate more stable effects that could be maintained in its absence and not depend on its expression for long term synaptic support.
It was previously mentioned that AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
receptor expression is essential to learning and memory formation, as these are the components of the synapse that will communicate regularly and maintain the synapse structure and function long after the initial activation of NMDA channels. BDNF is capable of increasing the mRNA expression of GluR1 and GluR2 through its interaction with the TrkB receptor and promoting the synaptic localization of GluR1
Glutamate receptor 1 is a protein that in humans is encoded by the ''GRIA1'' gene.
Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophy ...
via PKC- and CaMKII-mediated Ser-831 phosphorylation. It also appears that BDNF is able to influence Gl1 activity through its effects on NMDA receptor activity. BDNF significantly enhanced the activation of GluR1 through phosphorylation of tyrosine830, an effect that was abolished in either the presence of a specific NR2B
Glutamate MDAreceptor subunit epsilon-2, also known as ''N''-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the ''GRIN2B'' gene.
NMDA receptors
''N''-methyl-D-aspartate (NMDA) receptors are ...
antagonist or a trk receptor tyrosine kinase inhibitor. Thus, it appears BDNF can upregulate the expression and synaptic localization of AMPA receptors, as well as enhance their activity through its postsynaptic interactions with the NR2B subunit. This suggests BDNF is not only capable of initiating synapse formation through its effects on NMDA receptor activity, but it can also support the regular every-day signaling necessary for stable memory function.
GABAergic signaling
One mechanism through which BDNF appears to maintain elevated levels of neuronal excitation is through preventing GABAergic signaling activities. While glutamate is the brain's major excitatory neurotransmitter and phosphorylation normally activates receptors, GABA is the brain's primary inhibitory neurotransmitter and phosphorylation of GABAA receptors tend to reduce their activity. Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions in spontaneous action potential
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, ...
frequencies that were mediated by an increase in the amplitude of GABAergic inhibitory postsynaptic currents (IPSC). Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.
This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB. Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition. In support of this putative mechanism, activation of PKCε leads to phosphorylation of N-ethylmaleimide-sensitive factor (NSF) at serine 460 and threonine 461, increasing its ATPase activity which downregulates GABAA receptor surface expression and subsequently attenuates inhibitory currents.
Synaptogenesis
BDNF also enhances synaptogenesis. Synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...
is dependent upon the assembly of new synapses and the disassembly of old synapses by β-adducin. Adducins are membrane-skeletal proteins that cap the growing ends of actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
filaments and promote their association with spectrin, another cytoskeletal protein, to create stable and integrated cytoskeletal networks. Actins have a variety of roles in synaptic functioning. In pre-synaptic neurons, actins are involved in synaptic vesicle recruitment and vesicle recovery following neurotransmitter release. In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal. At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity. BDNF can reduce capping activities by upregulating PKC, which can bind to the adducing MRCKS domain, inhibit capping activity, and promote synaptogenesis through dendritic spine growth and disassembly and other activities.
Dendritogenesis
Local interaction of BDNF with the TrkB receptor on a single dendritic segment is able to stimulate an increase in PSD-95 trafficking to other separate dendrites as well as to the synapses of locally stimulated neurons. PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
localizes the actin-remodeling GTPases, Rac and Rho
Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
, to synapses through the binding of its PDZ domain to kalirin
Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the ''KALRN'' gene. Kaliri ...
, increasing the number and size of spines. Thus, BDNF-induced trafficking of PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.
Neurogenesis
BDNF plays a significant role in neurogenesis. BDNF can promote protective pathways and inhibit damaging pathways in the NSCs and NPCs that contribute to the brain's neurogenic response by enhancing cell survival. This becomes especially evident following suppression of TrkB activity. TrkB inhibition results in a 2–3 fold increase in cortical precursors displaying EGFP-positive condensed apoptotic nuclei and a 2–4 fold increase in cortical precursors that stained immunopositive for cleaved caspase-3
Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also p ...
. BDNF can also promote NSC and NPC proliferation through Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
activation and PTEN inactivation. There have been many in vivo studies demonstrating BDNF is a strong promoter of neuronal differentiation. Infusion of BDNF into the lateral ventricles doubled the population of newborn neurons in the adult rat olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
and viral overexpression of BDNF can similarly enhance SVZ neurogenesis. BDNF might also play a role in NSC/NPC migration. By stabilizing p35 (CDK5R1), in utero electroporation studies revealed BDNF was able to promote cortical radial migration by ~230% in embryonic rats, an effect which was dependent on the activity of the trkB receptor.
Cognitive function
Enriched housing provides the opportunity for exercise and exposure to multimodal stimuli. The increased visual, physical, and cognitive stimulation all translates into more neuronal activity and synaptic communication, which can produce structural or molecular activity-dependent alterations. Sensory inputs from environmental stimuli are initially processed by the cortex before being transmitted to the hippocampus along an afferent pathway, suggesting the activity-mediated effects of enrichment can be far-reaching within the brain.
BDNF expression is significantly enhanced by environmental enrichment and appears to be the primary source of the ability of environmental enrichments to enhance cognitive processes. Environmental enrichment enhances synaptogenesis, dendridogenesis, and neurogenesis, leading to improved performance on various learning and memory tasks. BDNF mediates more pathways involved in these enrichment-induced processes than any other molecule and is strongly regulated by calcium activity making it incredibly sensitive to neuronal activity.
Disease linkage
Various studies have shown possible links between BDNF and conditions, such as depression, schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
, obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
, Rett syndrome
Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...
, and dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
, as well as anorexia nervosa
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gr ...
and bulimia nervosa
Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging or fasting, and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten ...
.
Increased levels of BDNF can induce a change to an opiate-dependent-like reward state when expressed in the ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
in rats.
As of 2002 clinical trials in which BDNF was delivered into the central nervous system (CNS) of humans with various neurodegenerative disease had all failed.
Schizophrenia
A plethora of recent evidence suggests the linkage between schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
and BDNF. Given that BDNF is critical for the survival of central nervous system (CNS) and peripheral nervous system (PNS) neurons and synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...
during and even after development, BDNF alterations may play a role in the pathogenesis of schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
. BDNF has been found within many areas of the brain and plays an important role in supporting the formation of memories. It has been shown that BDNF mRNA levels are decreased in cortical layers IV and V of the dorsolateral prefrontal cortex of schizophrenic patients, an area that is known to be involved with working memory. Since patients with schizophrenia often have impairments in working memory, and BDNF mRNA levels have been shown to be decreased in the DLPFC of schizophrenic patients, it is highly likely that BDNF plays some role in the etiology of this neurodevelopmental disorder of the CNS.
Depression
The neurotrophic hypothesis of depression states that depression is caused by a decrease in the levels of BDNF. Post-mortem studies of depressed individuals have shown significantly lower levels of serum BDNF. It is possible that antidepressants, mainly SSRI
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s, are able to alleviate depressive symptoms by increasing BDNF levels, leading to higher levels of neural plasticity
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 ...
through the maintenance of new neural branches and synaptic connections.
Exposure to stress
Stress may refer to:
Science and medicine
* Stress (biology), an organism's response to a stressor such as an environmental condition
* Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
and the stress hormone corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rar ...
has been shown to decrease the expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of BDNF in rats, and, if exposure is persistent, this leads to an eventual atrophy of the 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 system, ...
. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans with chronic depression. In addition, rats bred to be heterozygous for BDNF, therefore reducing its expression, have been observed to exhibit similar hippocampal atrophy. This suggests that an etiological link between the development of depression and BDNF exists. Supporting this, the excitatory neurotransmitter glutamate, voluntary exercise, caloric restriction
Calorie restriction (caloric restriction or energy restriction) is a dietary regimen that reduces intake of energy from caloric foods & beverages without incurring malnutrition. "Reduce" can be defined relative to the subject's previous intake be ...
, intellectual stimulation, and various treatments for depression such as antidepressants
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
increase expression of BDNF in the brain. There is evidence that antidepressant drugs protect against or reverse hippocampal atrophy.
A recent study shows that downregulation of Nrf2-BDNF-TrkB signaling contributes to the development of post-intracerebral hemorrhage depression and that Nrf2 inducer TP-500 improves depression-like behaviors in this experimental condition.
Alzheimer's disease
Post mortem analysis has shown lowered levels of BDNF in the brain tissues of people with Alzheimer's disease, although the nature of the connection remains unclear. Studies suggest that neurotrophic factors have a protective role against amyloid beta toxicity.
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 electrica ...
has also been linked with polymorphisms in BDNF. Given BDNF's vital role in the development of the landscape of the brain, there is quite a lot of room for influence on the development of neuropathologies from BDNF. Levels of both BDNF mRNA and BDNF protein are known to be up-regulated in epilepsy. BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor-mediated post-synaptic currents. This provides a potential mechanism for the observed up-regulation.
Aging
BDNF levels appear to be highly regulated throughout the lifetime both in the early developmental stages and in the later stages of life. For example, BDNF appears to be critical for the morphological development such as dendrite
Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...
orientation and number along with soma size. This is important as neuron morphology is critical in behavioral processes like learning and motor skills development. Research has reported that the interaction between BDNF and TrkB
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...
(the receptor to BDNF) is highly important in inducing dendritic growth; some have noted that the phosphorylation of TrkB by another molecule, cdk5
Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS).
The molecule belongs ...
is necessary for this interaction to occur. Thus, high BDNF and active TrkB interaction appears to be necessary during a critical developmental period as it is regulatory in neuron morphology. The inhibition of BDNF signaling has been shown to alter the epigenetic status in hippocampal cells, with a strength increased by age.
Although BDNF is needed in the developmental stages, BDNF levels have been shown to decrease in tissues with aging. Studies using human subjects have found that hippocampal
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 system, an ...
volume decreases with decreasing plasma levels of BDNF. Although this does not mean BDNF necessarily impacts hippocampal volume, it does suggest there is a relationship that might explain some of the cognitive decline that occurs during aging.
Miscellaneous
BDNF is a critical mediator of vulnerability to stress, memory of fear/trauma, and stress-related disorders such as post-traumatic stress disorder.
Variants close to the BDNF gene were found to be associated with obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
in two very large genome-wide association studies of body mass index (BMI).
High levels of BDNF and Substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...
have been associated with increased itching in eczema
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can ...
.
BDNF is a regulator of drug addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
and psychological dependence
Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exp ...
. Animals chronically exposed to drugs of abuse show increased levels of BDNF in the ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
(VTA) of the brain, and when BDNF is injected directly into the VTA of rats, the animals act as if they are addicted to and psychologically dependent upon opiates.
BDNF is a short-term promoter, but a long-term inhibitor of pain sensitivity, as a result of its effect as inducer of neuronal differentiation. The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome
Central hypoventilation syndrome (CHS) is a sleep-related breathing disorder that causes ineffective breathing, apnea, or respiratory arrest during sleep (and during wakefulness in severe cases). CHS can either be congenital (CCHS) or acquired ( ...
. BDNF and IL-6 might be involved in the pathogenesis of post-chemotherapy cognitive impairment
Post-chemotherapy cognitive impairment (PCCI) (also known in the scientific community as "CRCIs or Chemotherapy-Related Cognitive Impairments" and in lay terms as chemotherapy-induced cognitive dysfunction or impairment, chemo brain, or chemo fog) ...
(PCCI, also known as chemo brain) and fatigue.
See also
* Epigenetics of depression § Brain-derived neurotrophic factor
* Epigenetics of schizophrenia § Methylation of BDNF
* Tropomyosin receptor kinase B § Agonists
References
External links
*
*
*
*
*
{{DEFAULTSORT:Brain-Derived Neurotrophic Factor
Neurotrophic factors
Peptide hormones
Growth factors
Developmental neuroscience
TrkB agonists