Brain-derived neurotrophic factor
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Brain-derived neurotrophic factor also known as BDNF is a protein[1] encoded by the BDNF gene.[2][3] 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.
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[edit] 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.[4][5] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.[6] BDNF itself is important for long-term memory.[7] 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.[8][9][10] 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.[11]
[edit] 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 central nervous system, motor neurons, the kidneys, and the prostate.[citation needed]
[edit] 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).[12] It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor.[13]
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.[12]
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.[citation needed] 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.[citation needed]
[edit] Interactions
BDNF has been shown to interact with the reelin signaling chain.[14] The expression of reelin by Cajal-Retzius cells goes down during development under the influence of BDNF.[15] The latter also decreases reelin expression in neuronal culture.
[edit] Secretion
BDNF is made in the endoplasmic reticulum and secreted from dense core vesicles. It binds the sorting receptor carboxypeptidase E (CPE) and the disruption of this binding causes loss of sorting of BDNF into dense core vesicles. However, knockout animal studies showed no deficit.
Exercise has been shown to increase the secretion of BDNF at the mRNA and protein levels in the rodent hippocampus, suggesting the potential increase of this neurotrophin after exercise in humans.[16]
[edit] Genetics
The BDNF protein is coded by the gene that is also called BDNF. In humans this gene is located on chromosome 11.[2][3] 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.[17][18]
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.[citation needed]
The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome.[19][20]
[edit] 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.[21][citation needed]
Furthermore, increased levels of BDNF can induce a change to an opiate-dependent state when expressed in the ventral tegmental area[22] in rats, leading to the possibility that this mechanism partially underlies physical opiate dependence. In fact, BDNF can actually change the GABAa receptor from being inhibitory to excitatory in this area, a possible psychical mechanism underlying drug-seeking behavior[23].
[edit] 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.[24] 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,[25] 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.[citation needed]
[edit] Eczema
High levels of BDNF and Substance P have been found associated with increased itching in eczema.[26]
[edit] 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.[27] BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor mediated post-synaptic currents.[28] This provides a potential mechanism for the observed up-regulation.
[edit] References
- ^ Binder DK, Scharfman HE (September 2004). "Brain-derived neurotrophic factor". Growth Factors 22 (3): 123–31. doi:. PMID 15518235.
- ^ a b Jones KR, Reichardt LF (October 1990). "Molecular cloning of a human gene that is a member of the nerve growth factor family". Proc. Natl. Acad. Sci. U.S.A. 87 (20): 8060–4. doi:. PMID 2236018. PMC: 54892. http://www.pnas.org/content/87/20/8060.
- ^ a b Maisonpierre PC, Le Beau MM, Espinosa R, 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:. PMID 1889806.
- ^ Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM (March 1995). "A BDNF autocrine loop in adult sensory neurons prevents cell death". Nature 374 (6521): 450–3. doi:. PMID 7700353.
- ^ Huang EJ, Reichardt LF (2001). "Neurotrophins: roles in neuronal development and function". Annu. Rev. Neurosci. 24: 677–736. doi:. PMID 11520916.
- ^ Yamada K, Nabeshima T (April 2003). "Brain-derived neurotrophic factor/TrkB signaling in memory processes". J. Pharmacol. Sci. 91 (4): 267–70. doi:. PMID 12719654.
- ^ Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (February 2008). "BDNF is essential to promote persistence of long-term memory storage". Proc. Natl. Acad. Sci. U.S.A. 105 (7): 2711–6. doi:. PMID 18263738.
- ^ Zigova T, Pencea V, Wiegand SJ, Luskin MB (July 1998). "Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb". Mol. Cell. Neurosci. 11 (4): 234–45. doi:. PMID 9675054.
- ^ Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA (01 September 2001). "Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain". J. Neurosci. 21 (17): 6718–31. PMID 11517261. http://www.jneurosci.org/cgi/content/abstract/21/17/6718.
- ^ Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (01 September 2001). "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". J. Neurosci. 21 (17): 6706–17. PMID 11517260. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11517260.
- ^ Ernfors P, Kucera J, Lee KF, Loring J, Jaenisch R (October 1995). "Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice". Int. J. Dev. Biol. 39 (5): 799–807. PMID 8645564. http://www.intjdevbiol.com/paper.php?doi=8645564.
- ^ a b Patapoutian A, Reichardt LF (June 2001). "Trk receptors: mediators of neurotrophin action". Curr. Opin. Neurobiol. 11 (3): 272–80. doi:. PMID 11399424.
- ^ Fernandes CC, Pinto-Duarte A, Ribeiro JA, Sebastião AM (May 2008). "Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons". J. Neurosci. 28 (21): 5611–8. doi:. PMID 18495895.
- ^ Fatemi, S. Hossein (2008). Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease. Berlin: Springer. pp. 444 pages. ISBN 978-0-387-76760-4. http://www.springer.com/biomed/neuroscience/book/978-0-387-76760-4.; see the chapter "A Tale of Two Genes: Reelin and BDNF"; pp. 237-245
- ^ Ringstedt T, Linnarsson S, Wagner J, Lendahl U, Kokaia Z, Arenas E, Ernfors P, Ibáñez CF (August 1998). "BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex". Neuron 21 (2): 305–15. PMID 9728912. http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)80540-1.
- ^ Cotman CW, Berchtold NC (June 2002). "Exercise: a behavioral intervention to enhance brain health and plasticity". Trends Neurosci. 25 (6): 295–301. doi:. PMID 12086747. http://linkinghub.elsevier.com/retrieve/pii/S0166223602021434.
- ^ Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (January 2003). "The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function". Cell 112 (2): 257–69. doi:. PMID 12553913.
- ^ Bath KG, Lee FS (March 2006). "Variant BDNF (Val66Met) impact on brain structure and function" ([dead link] – Scholar search). Cogn Affect Behav Neurosci 6 (1): 79–85. doi:. PMID 16869232. http://www.ingentaconnect.com/content/psocpubs/cabn/2006/00000006/00000001/art00009.
- ^ Omim - Brain-Derived Neurotrophic Factor; Bdnf
- ^ Weese-Mayer DE, Bolk S, Silvestri JM, Chakravarti A (2002). "Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation". Am. J. Med. Genet. 107: 306–310. doi:. PMID 11840487.
- ^ Strand AD, Baquet ZC, Aragaki AK, et al. (October 2007). "Expression profiling of Huntington's disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration". J Neurosci 27 (43): 11758–68. doi:. PMID 17959817.
- ^ Varga-Perez H, Ting-A Kee R, Walton C, et al. (June 2009). "Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats". Science 324 (5935): 1732-34. doi:.
- ^ Varga-Perez H, Ting-A Kee R, Walton C, et al. (June 2009). "Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats". Science 324 (5935): 1732-34. doi:.
- ^ Warner-Schmidt JL, Duman RS (2006). "Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment". Hippocampus 16 (3): 239–49. doi:. PMID 16425236.
- ^ Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW (2000). "Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus". Neuroscience 101 (2): 305–12. doi:. PMID 11074154.
- ^ BBC (2007-08-26). "'Blood chemicals link' to eczema". BBC NEWS. http://news.bbc.co.uk/2/hi/health/6962450.stm.
- ^ 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 Res. Suppl. 4: 225–45. PMID 1815605.
- ^ Tanaka T, Saito H, Matsuki N (01 May 1997). "Inhibition of GABAA synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus". J. Neurosci. 17 (9): 2959–66. PMID 9096132. http://www.jneurosci.org/cgi/content/abstract/17/9/2959.
[edit] External links
- Cotman CW, Berchtold NC (2004-01-28). "BDNF and Alzheimer's Disease—What's the Connection?". Alzforum: Live Discussions. Alzheimer Research Forum. http://www.alzforum.org/res/for/journal/cotman/default.asp. Retrieved on 2008-08-21.
- Patten-Hitt E (2001-06-14). "Brain-Derived Neurotrophic Factor (BDNF)". Sciencexpress. The HDLighthouse, Huntingtons Disease: Information and Community. http://hdlighthouse.org/see/research/bdnf.htm. Retrieved on 2008-08-21.
- Highfield R (2007-10-18). "Brain scans 'could reveal mental strength'". Science. Telegraph.co.uk. http://www.telegraph.co.uk/earth/main.jhtml?view=DETAILS&grid=&xml=/earth/2007/10/18/scistress118.xml. Retrieved on 2008-08-21. "Low BDNF activity promotes resilience"
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