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Brain-derived neurotrophic factor (BDNF) is a human gene.[1][2] The protein encoded by this gene is a neurotrophic factor found in the brain and the periphery. It is a protein that 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. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. 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. 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.
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.
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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). It also might bind to nicotinic acetylcholine receptor alpha7.[3]
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. 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.
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.
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
The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome.[4][5]
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. [6]citation needed
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.[7] 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,[8] 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
Eczema
High levels of BDNF and Substance P have been found associated with increased itching in eczema.[9]
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.[10] BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor mediated post-synaptic currents. This provides a potential reason for the observed up-regulation.
References
- ^ 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. PMID 2236018. PMC:54892.
- ^ 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. PMID 1889806.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
Further reading
- 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.
- Jones KR, Fariñas I, Backus C, Reichardt LF (1994). "Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development". Cell 76 (6): 989–99. doi:. PMID 8137432.
- Arévalo JC, Waite J, Rajagopal R, et al (2006). "Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination". Neuron 50 (4): 549–59. doi:. PMID 16701206.
- Yamada K, Nabeshima T (2004). "Brain-derived neurotrophic factor/TrkB signaling in memory processes". J. Pharmacol. Sci. 91 (4): 267–70. PMID 12719654.
- Pang PT, Lu B (2005). "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Res. Rev. 3 (4): 407–30. doi:. PMID 15541709.
- Hashimoto K, Koizumi H, Nakazato M, et al. (2005). "Role of brain-derived neurotrophic factor in eating disorders: recent findings and its pathophysiological implications". Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (4): 499–504. doi:. PMID 15866349.
- Tsai SJ (2007). "Increased central brain-derived neurotrophic factor activity could be a risk factor for substance abuse: Implications for treatment". Med. Hypotheses 68 (2): 410–4. doi:. PMID 16824691.
- Bath KG, Lee FS (2006). "Variant BDNF (Val66Met) impact on brain structure and function". Cognitive, affective & behavioral neuroscience 6 (1): 79–85. PMID 16869232.
- Nair A, Vaidya VA (2006). "Cyclic AMP response element binding protein and brain-derived neurotrophic factor: molecules that modulate our mood?". J. Biosci. 31 (3): 423–34. doi:. PMID 17006024.
External links
- Cotman CW, Berchtold NC (2004-01-28). "BDNF and Alzheimer's Disease—What's the Connection?". Alzforum: Live Discussions. Alzheimer Research Forum. Retrieved on 2008-08-21.
- Patten-Hitt E (2001-06-14). "Brain-Derived Neurotrophic Factor (BDNF)". Sciencexpress. The HDLighthouse, Huntingtons Disease: Information and Community. Retrieved on 2008-08-21.
- Highfield R (2007-10-18). "Brain scans 'could reveal mental strength'". Science. Telegraph.co.uk. Retrieved on 2008-08-21. “Low BDNF activity promotes resilience”
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- This page was last modified on 21 August 2008, at 15:48.
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