Brain-derived neurotrophic factor

Brain-derived neurotrophic factor, also known as BDNF, is a is_associated_with::protein that, in humans, is encoded by the BDNF is_associated_with::gene. BDNF is a member of the is_associated_with::neurotrophin family of growth factors, which are related to the canonical is_associated_with::Nerve Growth Factor. is_associated_with::Neurotrophic factors are found in the is_associated_with::brain and the periphery.

Function
BDNF acts on certain is_associated_with::neurons of the is_associated_with::central nervous system and the is_associated_with::peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and is_associated_with::synapses. In the brain, it is active in the is_associated_with::hippocampus, cortex, and is_associated_with::basal forebrain—areas vital to is_associated_with::learning, is_associated_with::memory, and higher thinking. It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate.

BDNF itself is important for is_associated_with::long-term memory. Although the vast majority of neurons in the is_associated_with::mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural is_associated_with::stem cells in a process known as is_associated_with::neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF suffer developmental defects in the brain and is_associated_with::sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal is_associated_with::neural development. Other important neurotrophins structurally related to BDNF include is_associated_with::NT-3, is_associated_with::NT-4, and NGF.

BDNF is made in the is_associated_with::endoplasmic reticulum and secreted from dense-core vesicles. It binds is_associated_with::carboxypeptidase E (CPE), and the disruption of this binding has been proposed to cause the loss of sorting of BDNF into dense-core vesicles. The is_associated_with::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.

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 appears to upregulate BDNF and is_associated_with::tropomyosin receptor kinase B (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, is_associated_with::TrkB (pronounced "Track B") and the is_associated_with::LNGFR (for low-affinity nerve growth factor receptor, also known as p75). It may also modulate the activity of various neurotransmitter receptors, including the is_associated_with::Alpha-7 nicotinic receptor. BDNF has also been shown to interact with the is_associated_with::reelin signaling chain. The expression of reelin by is_associated_with::Cajal-Retzius cells 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 is_associated_with::NTRK2 gene and is member of a receptor family of tyrosine kinases that includes is_associated_with::TrkA and is_associated_with::TrkC. These receptors all interact with neurotrophins in a is_associated_with::ligand-specific manner. TrkB is_associated_with::autophosphorylation is dependent upon its ligand-specific association with BDNF, a widely expressed activity-dependent neurotrophic factor that regulates is_associated_with::neuroplasticity and is upregulated following hypoxic injury.

LNGFR
The role of the other BDNF receptor, is_associated_with::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 is_associated_with::NFkB receptor. Thus, neurotrophic signaling may trigger is_associated_with::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 the 8 untranslated 5’ promoter exons spliced to the 3’ encoding is_associated_with::exon. Promoter IV activity is strongly stimulated by calcium and is primarily under the control of a Cre regulatory component, suggesting a putative role for the transcription factor is_associated_with::CREB and the source of BDNF’s activity-dependent effects. There are multiple mechanisms through neuronal activity 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, is_associated_with::PI3K, and PLC, is_associated_with::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 is_associated_with::basic helix-loop-helix transcription factor protein 2 (is_associated_with::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 is_associated_with::Dopamine receptor D5 also promotes expression of BDNF in is_associated_with::prefrontal cortex neurons.

is_associated_with::Val66Met (rs6265) is a is_associated_with::single nucleotide polymorphism in the gene where is_associated_with::adenine and is_associated_with::guanine is_associated_with::alleles vary, resulting in a variation between is_associated_with::valine and is_associated_with::methionine at is_associated_with::codon 66. As of 2008, Val66Met is probably the most investigated SNP of the BDNF gene, but, besides this variant, other SNPs in the gene are C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442.

Glutamatergic signaling
is_associated_with::Glutamate is the brain’s major excitatory is_associated_with::neurotransmitter and its release can trigger the is_associated_with::depolarization of is_associated_with::postsynaptic neurons. is_associated_with::AMPA and is_associated_with::NMDA receptors are two major is_associated_with::ionotropic receptors that are especially suspected of being involved in learning and memory. While AMPA receptor activation leads to depolarization via sodium influx, NMDA receptor activation leads to depolarization via calcium and sodium influx. The calcium influx triggered through NMDA receptors can lead to the activity-dependent expression of many different genes, proteins, and receptors that are thought to be involved in processes involving learning, memory, neurogenesis, and environmental responses. The activity-dependent synaptic responses also lead to rapid insertion of AMPA receptors into the postsynaptic membrane, which will act to maintain ongoing glutamatergic transmission as sustained calcium influx could result in excitotoxicity

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 completely eliminated receptor activity. BDNF can also increase NMDA receptor activity through phosphorylation of the is_associated_with::NR2B subunit. BDNF signaling leads to the autophosphorylation of the intracellular domain of the TrkB receptor (ICD-TrkB). Upon autophosphorylation, is_associated_with::Fyn 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 is_associated_with::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 is_associated_with::GluR1 via PKC- and CaMKII-mediated Ser-831 phosphorylation. It also appears that BDNF is able to influence is_associated_with::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 is_associated_with::NR2B 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 is_associated_with::GABAergic signaling activities. While glutamate is the brain’s major excitatory neurotransmitter and phosphorylation normally activates receptors, is_associated_with::GABA is the brain’s primary inhibitory neurotransmitter and phoshorylation of is_associated_with::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 is_associated_with::action potential 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 of 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 is also enhances synaptogenesis. is_associated_with::Synaptogenesis 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 is_associated_with::actin 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 synatogenesis through dendritic spine growth and disassembly and other activities.

Dendridogenesis
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. is_associated_with::PSD-95 localizes the actin-remodeling GTPases, Rac and is_associated_with::Rho, to synapses through the binding of its PDZ domain to is_associated_with::kalirin, increasing the number and size of spines. Thus, BDNF-induced trafficking of is_associated_with::PSD-95 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 is_associated_with::caspase-3. BDNF can also promote NSC and NPC proliferation through is_associated_with::Akt 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 is_associated_with::olfactory bulb 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 about 2.3-fold 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 environmental enrichments ability 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, is_associated_with::schizophrenia, is_associated_with::obsessive-compulsive disorder, is_associated_with::Alzheimer's disease, is_associated_with::Huntington's disease, is_associated_with::Rett syndrome, and is_associated_with::dementia, as well as is_associated_with::anorexia nervosa and is_associated_with::bulimia nervosa. Increased levels of BDNF can induce a change to an opiate-dependent-like reward state when expressed in the is_associated_with::ventral tegmental area in rats.

Schizophrenia
A plethora of recent evidence suggests the linkage between is_associated_with::schizophrenia and BDNF. Given that BDNF is critical for the survival of central nervous system (CNS) and peripheral nervous system (PNS) neurons and is_associated_with::synaptogenesis during and even after development, BDNF alterations may play a role in the pathogenesis of is_associated_with::schizophrenia. BDNF has been found within many areas of the brain and plays an important role is 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 schizophrenic patients often suffer from 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
Exposure to stress and the stress hormone is_associated_with::corticosterone has been shown to decrease the expression of BDNF in rats, and, if exposure is persistent, this leads to an eventual atrophy of the is_associated_with::hippocampus. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from 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 is_associated_with::glutamate, voluntary is_associated_with::exercise, is_associated_with::caloric restriction, intellectual stimulation, is_associated_with::curcumin and various treatments for depression (such as is_associated_with::antidepressants and is_associated_with::electroconvulsive therapy ) increase expression of BDNF in the brain. In the case of some treatments such as drugs and electroconvulsive therapy this has been shown to protect or reverse this atrophy.

Eczema
High levels of BDNF and is_associated_with::Substance P have been associated with increased itching in is_associated_with::eczema.

Epilepsy
is_associated_with::Epilepsy 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.

Alzheimer's disease
Post mortem analysis has shown lowered levels of BDNF in the brain tissues of people with is_associated_with::Alzheimer's disease, although the nature of the connection remains unclear. Studies suggest that neurotrophic factors have a protective role against is_associated_with::amyloid beta toxicity.

Drug addiction and dependence
BDNF is a regulator of drug is_associated_with::addiction and is_associated_with::psychological dependence. Animals chronically exposed to drugs of abuse show increased levels of BDNF in the ventral tegmental area (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.

Obesity
In 2009, variants close to the BDNF gene were found to be associated with is_associated_with::obesity in two very large genome-wide association studies of is_associated_with::body mass index (BMI).

Aging
BDNF levels decrease during aging.

Congenital central hypoventilation syndrome
The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome.

Post-chemotherapy cognitive impairment
BDNF and IL-6 might be involved in the pathogenesis of is_associated_with::post-chemotherapy cognitive impairment (PCCI, also known as chemo brain) and fatigue.