Brain-derived neurotrophic factor

Brain-derived neurotrophic factor also known as BDNF is a proteincite journal | author = Binder DK, Scharfman HE | title = Brain-derived neurotrophic factor | journal = Growth Factors | volume = 22 | issue = 3 | pages = 123–31 | year = 2004 | month = September | pmid = 15518235 | pmc = 2504526 | doi = 10.1080/08977190410001723308 | url = ] encoded by the "BDNF" gene.cite journal | author = Jones KR, Reichardt LF | title = Molecular cloning of a human gene that is a member of the nerve growth factor family | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 20 | pages = 8060–4 | year = 1990 | month = October | pmid = 2236018 | pmc = 54892 | url = http://www.pnas.org/content/87/20/8060 | doi = 10.1073/pnas.87.20.8060 ] cite journal | author = Maisonpierre PC, Le Beau MM, Espinosa R, "et al" | title = Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations | journal = Genomics | volume = 10 | issue = 3 | pages = 558–68 | year = 1991 | month = July | pmid = 1889806 | url = | doi = 10.1016/0888-7543(91)90436-I ] BDNF is a member of the "neurotrophin" family of growth factors – which are related to the canonical "Nerve Growth Factor", NGF. Neurotrophic factors are found in the brain and the periphery.

Function

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses.cite journal | author = Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM | title = A BDNF autocrine loop in adult sensory neurons prevents cell death | journal = Nature | volume = 374 | issue = 6521 | pages = 450–3 | year = 1995 | month = March | pmid = 7700353 | doi = 10.1038/374450a0 | url = ] cite journal | author = Huang EJ, Reichardt LF | title = Neurotrophins: roles in neuronal development and function | journal = Annu. Rev. Neurosci. | volume = 24 | issue = | pages = 677–736 | year = 2001 | pmid = 11520916 | doi = 10.1146/annurev.neuro.24.1.677 | url = ] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.cite journal | author = Yamada K, Nabeshima T | title = Brain-derived neurotrophic factor/TrkB signaling in memory processes | journal = J. Pharmacol. Sci. | volume = 91 | issue = 4 | pages = 267–70 | year = 2003 | month = April | pmid = 12719654 | doi = 10.1254/jphs.91.267 | url = ] BDNF itself is important for long-term memory.cite journal | author = Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH | title = BDNF is essential to promote persistence of long-term memory storage | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 7 | pages = 2711–6 | year = 2008 | month = February | pmid = 18263738 | pmc = 2268201 | doi = 10.1073/pnas.0711863105 | url = ] BDNF was the second neurotrophic factor to be characterized after nerve growth factor (NGF).

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 chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active.cite journal | author = Zigova T, Pencea V, Wiegand SJ, Luskin MB | title = Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb | journal = Mol. Cell. Neurosci. | volume = 11 | issue = 4 | pages = 234–45 | year = 1998 | month = July | pmid = 9675054 | doi = 10.1006/mcne.1998.0684 | url = ] cite journal | author = Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA | title = Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain | journal = J. Neurosci. | volume = 21 | issue = 17 | pages = 6718–31 | year = 2001 | month = September | pmid = 11517261 | url = http://www.jneurosci.org/cgi/content/abstract/21/17/6718 | issn = ] cite journal | author = Pencea V, Bingaman KD, Wiegand SJ, Luskin MB | title = Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus | journal = J. Neurosci. | volume = 21 | issue = 17 | pages = 6706–17 | year = 2001 | month = September | pmid = 11517260 | url = http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11517260 | issn = ] Mice born without the ability to make BDNF suffer 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.cite journal | author = Ernfors P, Kucera J, Lee KF, Loring J, Jaenisch R | title = Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice | journal = Int. J. Dev. Biol. | volume = 39 | issue = 5 | pages = 799–807 | year = 1995 | month = October | pmid = 8645564 | url = http://www.intjdevbiol.com/paper.php?doi=8645564 | issn = ]

Tissue distribution

Despite its name, BDNF is actually found in a range of tissue and cell types, not just in the brain. It is also expressed in the retina, the CNS, motor neurons, the kidneys, and the prostate.Fact|date=August 2008

Mechanism of action

BDNF binds at least two receptors on the surface of cells which are capable of responding to this growth factor, TrkB (pronounced "Track B") and the LNGFR (for "low affinity nerve growth factor receptor", also known as p75).cite journal | author = Patapoutian A, Reichardt LF | title = Trk receptors: mediators of neurotrophin action | journal = Curr. Opin. Neurobiol. | volume = 11 | issue = 3 | pages = 272–80 | year = 2001 | month = June | pmid = 11399424 | doi = 10.1016/S0959-4388(00)00208-7 | url = ] It also might bind to the nAchR-α₇.cite journal | author = Fernandes CC, Pinto-Duarte A, Ribeiro JA, Sebastião AM | title = Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons | journal = J. Neurosci. | volume = 28 | issue = 21 | pages = 5611–8 | year = 2008 | month = May | pmid = 18495895 | doi = 10.1523/JNEUROSCI.5378-07.2008 | url = ]

TrkB is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkB mediates the effects of BDNF and NT-4, TrkA binds and is activated by NGF, and TrkC binds and is activated by NT-3. NT-3 binds to TrkA and TrkB as well, but with less affinity.

The other BDNF receptor, the p75, plays a somewhat less clear role. Some researchers have shown the p75NTR binds and serves as a "sink" for neurotrophins. Cells which express both the p75NTR and the Trk receptors might therefore have a greater activity - since they have a higher "microconcentration" of the neurotrophin.Fact|date=August 2008 It has also been shown, however, that the p75NTR may signal a cell to die via apoptosis - so therefore cells expressing the p75NTR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.Fact|date=August 2008

Secretion

BDNF is made in the ER and secreted from dense core vesicles (DCV). It binds the sorting receptor carboxypeptidase E (CPE) and the distruption of this binding causes loss of sorting of BDNF into DCVs. However, knockout (KO) animal studies showed no deficit.

Genetics

The BDNF protein is coded by the gene that is also called "BDNF".In humans this gene is located on chromosome 11.
Val66Met (rs6265) is a single nucleotide polymorphism in the gene where adenine and guanine alleles vary resulting in a variation between valine and methionine at codon 66.cite journal | author = Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR | title = The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function | journal = Cell | volume = 112 | issue = 2 | pages = 257–69 | year = 2003 | month = January | pmid = 12553913 | doi = 10.1016/S0092-8674(03)00035-7 | url = ] cite journal | author = Bath KG, Lee FS | title = Variant BDNF (Val66Met) impact on brain structure and function | journal = Cogn Affect Behav Neurosci | volume = 6 | issue = 1 | pages = 79–85 | year = 2006 | month = March | pmid = 16869232 | url = http://www.ingentaconnect.com/content/psocpubs/cabn/2006/00000006/00000001/art00009 | issn = ]

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.Fact|date=August 2008

The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome. [ [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=113505&a=113505_AllelicVariant0001 Omim - Brain-Derived Neurotrophic Factor; Bdnf ] ] [Cite journal
author = Weese-Mayer DE, Bolk S, Silvestri JM, Chakravarti A
title = Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation
journal = Am. J. Med. Genet.
volume = 107
pages = 306–310
year = 2002
pmid = 11840487
doi = 10.1002/ajmg.10133]

Disease linkage

Various studies have shown possible links between low levels of BDNF and conditions such as depression, schizophrenia, Obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease, Rett syndrome, and dementia, as well as anorexia nervosa and bulimia nervosa, though it is still not known whether these levels represent a cause or a symptom.cite journal |author=Strand AD, Baquet ZC, Aragaki AK, "et al" |title=Expression profiling of Huntington's disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration |journal=J Neurosci |volume=27 |issue=43 |pages=11758–68 |year=2007 |month=October |pmid=17959817 |doi=10.1523/JNEUROSCI.2461-07.2007 |url=] Fact|date=July 2007

Depression

Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and leads to an eventual atrophy of the hippocampus if exposure is persistent. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from chronic depression.cite journal | author = Warner-Schmidt JL, Duman RS | title = Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment | journal = Hippocampus | volume = 16 | issue = 3 | pages = 239–49 | year = 2006 | pmid = 16425236 | doi = 10.1002/hipo.20156 | url = ] In addition, rats bred to be heterozygous for BDNF, therefore reducing its expression, have been observed to exhibit similar hippocampal atrophy, suggesting that an etiological link between the development of depressive illness and regulation of BDNF exists. On the other hand, the excitatory neurotransmitter glutamate, voluntary exercise, [cite journal |author=Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW |title=Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus |journal=Neuroscience |volume=101 |issue=2 |pages=305–12 |year=2000 |pmid=11074154|doi=10.1016/S0306-4522(00)00349-3] caloric restriction, intellectual stimulation, curcumin and various treatments for depression (such as antidepressants and electroconvulsive therapy) strongly increase expression of BDNF in the brain, and have been shown to protect against this atrophy.Fact|date=October 2007

Eczema

High levels of BDNF and Substance P have been found associated with increased itching in eczema. [Cite news
author = BBC
title = 'Blood chemicals link' to eczema
url = http://news.bbc.co.uk/2/hi/health/6962450.stm
date = 2007-08-26
publisher = BBC NEWS]

Epilepsy

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.cite journal | author = Gall C, Lauterborn J, Bundman M, Murray K, Isackson P | title = Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain | journal = Epilepsy Res. Suppl. | volume = 4 | issue = | pages = 225–45 | year = 1991 | pmid = 1815605 | url = | issn = ] BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor mediated post-synaptic currents.cite journal | author = Tanaka T, Saito H, Matsuki N | title = Inhibition of GABAA synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus | journal = J. Neurosci. | volume = 17 | issue = 9 | pages = 2959–66 | year = 1997 | month = May | pmid = 9096132 | url = http://www.jneurosci.org/cgi/content/abstract/17/9/2959 | issn = ] This provides a potential mechanism for the observed up-regulation.

References

External links

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*cite web | url = http://hdlighthouse.org/see/research/bdnf.htm | title = Brain-Derived Neurotrophic Factor (BDNF) | author = Patten-Hitt E | authorlink = | coauthors = | date = 2001-06-14 | format = | work = Sciencexpress | publisher = The HDLighthouse, Huntingtons Disease: Information and Community | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-21
*cite web | url = http://www.telegraph.co.uk/earth/main.jhtml?view=DETAILS&grid=&xml=/earth/2007/10/18/scistress118.xml | title = Brain scans 'could reveal mental strength' | author = Highfield R | authorlink = | coauthors = | date = 2007-10-18 | format = | work = Science | publisher = Telegraph.co.uk | pages = | language = | archiveurl = | archivedate = | quote = Low BDNF activity promotes resilience | accessdate = 2008-08-21

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