Brain-derived neurotrophic factor (BDNF), or abrineurin,[5] is a
protein[6] that, in humans, is encoded by the BDNFgene.[7][8] 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 and
NT-4/NT-5.
Neurotrophic factors are found in the
brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.[9]
BDNF itself is important for
long-term memory.[17]
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.[18][19][20] Mice born without the ability to make BDNF have developmental defects in the brain and
sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal
neural development.[21] Other important neurotrophins structurally related to BDNF include
NT-3,
NT-4, and
NGF.
BDNF is made in the
endoplasmic reticulum and secreted from
dense-core vesicles. It binds
carboxypeptidase E (CPE), and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense-core vesicles. The
phenotype 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.[22]
BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor,
TrkB (pronounced "Track B")[10][11] and the
LNGFR (for low-affinity nerve growth factor receptor, also known as p75).[28] It may also modulate the activity of various neurotransmitter receptors, including the
Alpha-7 nicotinic receptor.[29] BDNF has also been shown to interact with the
reelin signaling chain.[30] The expression of reelin by
Cajal–Retzius cells goes down during development under the influence of BDNF.[31] 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 and
TrkC. TrkB
autophosphorylation is dependent upon its ligand-specific association with BDNF,[10][11] a widely expressed activity-dependent neurotrophic factor that regulates
plasticity and is dysregulated following
hypoxic injury. The activation of the BDNF-TrkB pathway is important in the development of short-term memory and the growth of neurons.[citation needed]
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.[32] When the p75 receptor is activated, it leads to activation of
NFkB receptor.[32] 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.[33]
Expression
The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11.[7][8] Structurally, BDNF transcription is controlled by eight different promoters, each leading to different transcripts containing one of eight 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 and the source of BDNF's activity-dependent effects .[34]
There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression.[34] 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, 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.[34][35] 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.[36] 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 transcription factor protein 2 (
BHLHB2).[37] 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.[37] Activation of
dopamine receptor D5 also promotes expression of BDNF in
prefrontal cortex neurons.[38]
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 is the most investigated
SNP of the BDNF gene [39][40]
Val66Met
A common
SNP in the BDNF gene is rs6265.[41] 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.[41][40] Val66Met is unique to humans.[41][40]
The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation.[41] 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.[41][40][42]
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,[40]anxiety disorders,[43]major depression,[44] and neurodegenerative diseases such as Alzheimer's and
Parkinson's.[45]
A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.[46]
Role in synaptic transmission
Glutamatergic signaling
Glutamate is the brain's major excitatory
neurotransmitter and its release can trigger the
depolarization of
postsynaptic neurons.
AMPA and
NMDA receptors are two
ionotropic glutamate receptors involved in
glutamatergic neurotransmission and essential to learning and memory via
long-term potentiation. 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.[47][48] 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.[47] 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.[47] PI3 kinase and Akt are also essential in BDNF-induced potentiation of NMDA receptor function and inhibition of either molecule eliminated receptor BDNF can also increase NMDA receptor activity through phosphorylation of the
NR2B subunit. BDNF signaling leads to the autophosphorylation of the intracellular domain of the TrkB receptor (ICD-TrkB). Upon autophosphorylation,
Fyn associates with the pICD-TrkB through its
Src homology domain 2 (SH2) and is phosphorylated at its Y416 site.[49][50] Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site.[51] Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus.[52][53] 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.[52]
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.[54]
It was previously mentioned that
AMPA 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 via PKC- and CaMKII-mediated Ser-831 phosphorylation.[55] It also appears that BDNF is able to influence
Gl1 activity through its effects on NMDA receptor activity.[56] BDNF significantly enhanced the activation of GluR1 through phosphorylation of tyrosine830, an effect that was abolished in either the presence of a specific
NR2B antagonist or a trk receptor tyrosine kinase inhibitor.[56] 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.[57] 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.[clarification needed] Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions in spontaneous
action potential frequencies that were mediated by an increase in the amplitude of GABAergic
inhibitory postsynaptic currents (IPSC).[57] Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.[57]
This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB.[57] Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition.[57] 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.[58]
Synaptogenesis
BDNF also enhances synaptogenesis.
Synaptogenesis is dependent upon the assembly of new synapses and the disassembly of old synapses by
β-adducin.[59] Adducins are membrane-skeletal proteins that cap the growing ends of
actin filaments and promote their association with spectrin, another cytoskeletal protein, to create stable and integrated cytoskeletal networks.[60] 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.[61] In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal.[61] At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity.[60] 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.[59][61]
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.[62]PSD-95 localizes the actin-remodeling GTPases,
Rac and
Rho, to synapses through the binding of its PDZ domain to
kalirin, increasing the number and size of spines.[63] Thus, BDNF-induced trafficking of
PSD-95 to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.
Neurogenesis
Laboratory studies indicate that BDNF may play a 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.[32] 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.[32] BDNF can also promote NSC and NPC proliferation through
Akt activation and
PTEN inactivation.[64] Some studies suggest that BDNF may promote neuronal differentiation.[32][65]
Preliminary studies have assessed a possible relationship between
schizophrenia and BDNF.[69] 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 associated with working memory.[70]
^
abMaisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM, et al. (July 1991). "Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations". Genomics. 10 (3): 558–68.
doi:
10.1016/0888-7543(91)90436-I.
PMID1889806.
^Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M, et al. (December 2010). "Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons". The European Journal of Neuroscience. 32 (11): 1854–65.
doi:
10.1111/j.1460-9568.2010.07460.x.
PMID20955473.
S2CID23496332.
^
abcSlack SE, Pezet S, McMahon SB, Thompson SW, Malcangio M (October 2004). "Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord". The European Journal of Neuroscience. 20 (7): 1769–78.
doi:
10.1111/j.1460-9568.2004.03656.x.
PMID15379998.
S2CID23108942.
^Xu X, Ye L, Ruan Q (March 2009). "Environmental enrichment induces synaptic structural modification after transient focal cerebral ischemia in rats". Experimental Biology and Medicine. 234 (3): 296–305.
doi:
10.3181/0804-RM-128.
PMID19244205.
S2CID39825785.
^
abWu K, Len GW, McAuliffe G, Ma C, Tai JP, Xu F, et al. (November 2004). "Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms". Brain Research. Molecular Brain Research. 130 (1–2): 178–86.
doi:
10.1016/j.molbrainres.2004.07.019.
PMID15519688.
^
abcdeHenneberger C, Jüttner R, Rothe T, Grantyn R (August 2002). "Postsynaptic action of BDNF on GABAergic synaptic transmission in the superficial layers of the mouse superior colliculus". Journal of Neurophysiology. 88 (2): 595–603.
doi:
10.1152/jn.2002.88.2.595.
PMID12163512.
S2CID9287511.
^
abMatsuoka Y, Li X, Bennett V (June 2000). "Adducin: structure, function and regulation". Cellular and Molecular Life Sciences. 57 (6): 884–95.
doi:
10.1007/pl00000731.
PMID10950304.
S2CID29317393.
^Yoshii A, Constantine-Paton M (June 2007). "BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation". Nature Neuroscience. 10 (6): 702–11.
doi:
10.1038/nn1903.
PMID17515902.
S2CID6486137.
^Xiong P, Zeng Y, Wu Q, Han Huang DX, Zainal H, Xu X, et al. (August 2014). "Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration". The Journal of Clinical Psychiatry. 75 (8): e794–801.
doi:
10.4088/JCP.13m08772.
PMID25191916.
^Gall C, Lauterborn J, Bundman M, Murray K, Isackson P (1991). "Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain". Epilepsy Research. Supplement. 4: 225–45.
PMID1815605.