Brain-derived neurotrophic factor

From Wikipedia, the free encyclopedia
  (Redirected from BDNF)
Jump to: navigation, search
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor - PDB id 1BND.png
PDB rendering based on 1bnd.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BDNF ; ANON2; BULN2
External IDs OMIM113505 MGI88145 HomoloGene7245 GeneCards: BDNF Gene
RNA expression pattern
PBB GE BDNF 206382 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 627 12064
Ensembl ENSG00000176697 ENSMUSG00000048482
UniProt P23560 P21237
RefSeq (mRNA) NM_001143805 NM_001048139
RefSeq (protein) NP_001137277 NP_001041604
Location (UCSC) Chr 11:
27.68 – 27.74 Mb
Chr 2:
109.67 – 109.73 Mb
PubMed search [1] [2]

Brain-derived neurotrophic factor, also known as BDNF, is a secreted protein[2] that, in humans, is encoded by the BDNF gene.[3][4] BDNF is a member of the "neurotrophin" family of growth factors and was the second neurotrophic factor to be characterized after nerve growth factor (NGF). These factors are found in the brain and the periphery; they support the survival of neurons and the growth of new ones.

Function[edit]

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.[5][6] In the brain, it is active in the hippocampus, cerebral cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.[7] BDNF itself is important for long-term memory.[8]

BDNF is expressed within the dentate gyrus and CA4-2 of the adult human. Allen Brain Atlases

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.[9][10][11]

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.[12] Other traits of BDNF knockout mice 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.[13]

In addition to its production and functions in the brain and nervous system, BDNF secreted by contracting skeletal muscle has been found to play a role in muscle repair, regeneration, and differentiation. BDNF can therefore now also be identified as a myokine that plays a role in peripheral metabolism, myogenesis, and muscle regeneration.[14]

Tissue distribution[edit]

Counterintuitively, 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] BDNF is present in high concentration in hippocampus and cerebral cortex. BDNF is also found in human saliva.[15]

Mechanism of action[edit]

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

BDNF binds to at least two receptors on the surface of cells that 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).[16] It may also modulate the activity of various neurotransmitter receptors, including the α7 nicotonic receptor.[17]

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 is the primary receptor for BDNF and NT-4, TrkA is the receptor for NGF, and TrkC is the primary receptor for NT-3. NT-3 binds to TrkA and TrkB as well, but with less affinity (thus the caveat "primary receptor").[16]

Caffeine improves recognition memory, and this effect may be related to an increase of the BDNF and TrkB immunocontent in the hippocampus.[18]

The other BDNF receptor, the p75, plays a somewhat less clear role. Some researchers have shown that the p75NTR binds and serves as a "sink" for neurotrophins. Cells that 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]

Effects of physical activity on cognition[edit]

Exercise has been shown to increase the secretion of BDNF as a myokine at the mRNA and protein levels in the rodent hippocampus, suggesting the potential increase of this neurotrophin after exercise in humans.[19][20] It is well known that BDNF increases in brain tissue in response to acute exercise and exercise training and may account for the effect of exercise in the protection against neurodegenerative diseases such as dementia. Additional benefits of exercise on brain function are also reported, including increases in grey and white matter in the prefrontal cortex and growth in hippocampal volume, with BDNF known to play a role in these effects.[21] Exercise induces an expression of BDNF in skeletal muscle, as well as in the brain.[14]

BDNF activity is correlated with increased long term potentiation and neurogenesis, which can be induced by physical activity.[22] Long term potentiation is shown to improve learning and memory by strengthening the communication between specific neurons. This was shown in the Morris water maze task in which the role of BDNF was tested in mice. One group of mice exercised on a running wheel while the control group of mice trained under standard conditions lacking physical exercise. When the groups of mice performed the Morris water maze task, the running group significantly increased their learning and memory by decreasing the latency in finding the platform.[22] Bromodeoxyuridine was injected into the mice to label dividing cells which proved to show that the physical exercise enhanced neurogenesis in the dentate gyrus of the hippocampus of the running mice, thus enhancing long term potentiation and memory.[23]

The increase in neurogenesis is hypothesized to increase learning in the mice.[23] MRI scans have shown that exercising mice have a selective increase in cerebral blood flow to the dentate gyrus of the hippocampus, an area of the brain particular to memory and learning, while there was no significant increase observed in other areas of the brain. The control mice group with no exercise did not have the same increase in the hippocampal region. This supporting evidence concludes that exercise selectively increases neurogenesis in the dentate gyrus of the hippocampus.[24]

The mechanism for this is due to BDNF activating the signal transduction cascades, MAP kinase and CAMKII, which regulate the expression of the transcription factor, CREB, and protein synapsin I. The mitochondria and the uncoupling protein, UCP2, which is mainly present in the brain’s mitochondria, have been thought to interact with this signal transduction cascade during physical activity. CREB and synapsin I both play a role in enhancing plasticity by changing the structure of the neuron and strengthening its signaling capability, therefore affecting long term potentiation. CREB specifically aids in spatial learning and regulating gene expression, while synapsin I modulates the release of neurotransmitters and affects the actin cytoskeleton of the cell which enhances the signaling capability of the neuron by changing its shape and density.[25]

Effects of diet on BDNF[edit]

Similar to exercise, both intermittent fasting and calorie restriction induce the production of brain derived neurotrophic factor, which in turn is associated with neurogenesis in the hippocampus.[26]

Effect of environmental enrichment on BDNF[edit]

Environmental enrichment, akin to intellectual activity in humans, is associated with some neuroprotective effects. Similar to exercise and dietary restriction, some of these effects are thought to be partially mediated by increased levels of BDNF. Levels of BDNF are increased in cerebral cortex, hippocampus, basal forebrain, and hindbrain of rats maintained in a complex environment.[27]

Genetics[edit]

The BDNF protein is coded by the gene that is also called BDNF. In humans this gene is located on chromosome 11.[3][4] 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.[28][29] A meta-analysis of association studies found no evidence that the Val66Met (rs6265) is associated with the level of BDNF in serum.[30]

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.[31][32]

In 2009, variants close to the BDNF gene were found to be associated with obesity in two very large genome wide-association studies of body mass index (BMI).[33][34]

Disease linkage[edit]

Various studies have shown possible links between BDNF and conditions such as depression,[35][36] bipolar disorder,[37] schizophrenia,[38] obsessive-compulsive disorder,[39] Alzheimer's disease,[40] Huntington's disease,[41] Rett syndrome,[42] and dementia,[43] as well as anorexia nervosa[44] and bulimia nervosa.[45]

Short bouts of exercise can produce an increase in serum BDNF which is hypothesized to be cancelled by exposure to air pollution.[46] In rodents, BDNF gene expression in the brain may also be down-regulated following exposure to air pollution.[20][47]

Inconclusive results have suggested the possibility of BDNF dysregulation in Autism Spectrum Disorders.[48][49][50]

Depression[edit]

Exposure to stress and the stress hormone 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 hippocampus. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from chronic depression.[51] In addition, rats bred to be heterozygous for BDNF, thereby reducing its expression, have been observed to exhibit similar hippocampal atrophy. This suggests an etiological link between the development of depression and BDNF. Supporting this, the excitatory neurotransmitter glutamate, voluntary exercise,[52] caloric restriction, intellectual stimulation, curcumin[53] and various treatments for depression (such as antidepressants[54] and electroconvulsive therapy[55] and sleep deprivation[56]) increase expression of BDNF in the brain. In the case of some treatments such as drugs[57] and electroconvulsive therapy,[58] this has been shown to protect or reverse this atrophy.[57]

Eczema[edit]

High levels of BDNF and Substance P have been found associated with increased itching in eczema.[59]

Epilepsy[edit]

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.[60] BDNF modulates excitatory and inhibitory synaptic transmission by inhibiting GABAA-receptor-mediated post-synaptic currents.[61] This provides a potential mechanism for the observed up-regulation.

Alzheimer's disease[edit]

Post mortem analysis has shown lowered levels of BDNF in the brain tissues of people with Alzheimer's disease, although the nature of the connection remains unclear. Studies suggest that neurotrophic factors have a protective role against amyloid beta toxicity. A connection between depression and dementia has been suggested to be mediated by BDNF. Depression causes shrinkage of the hippocampus. When antidepressants are administered, the levels of BDNF are raised to protect and increase the volume of hippocampal and other cells. In Alzheimer's, the hippocampus is also damaged, lowering levels of the neurotrophic factor.[62] Another possible link between BDNF and dementia is through fitness, since exercise can release BDNF and preserve cognition in older people.[63]

Drug addiction[edit]

BDNF is a critical regulator of drug dependency. 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 dependent on opiates.[64]

Interactions[edit]

BDNF has been shown to interact with TrkB.[65][66] BDNF has also been shown to interact with the reelin signaling chain.[67] The expression of reelin by Cajal-Retzius cells is decreased during development under the influence of BDNF.[68]

References[edit]

  1. ^ Robinson RC, Radziejewski C, Stuart DI, Jones EY (April 1995). "Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer". Biochemistry 34 (13): 4139–46. doi:10.1021/bi00013a001. PMID 7703225. 
  2. ^ Binder DK, Scharfman HE (September 2004). "Brain-derived Neurotrophic Factor". Growth Factors 22 (3): 123–31. doi:10.1080/08977190410001723308. PMC 2504526. PMID 15518235. 
  3. ^ 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. Bibcode:1990PNAS...87.8060J. doi:10.1073/pnas.87.20.8060. PMC 54892. PMID 2236018. 
  4. ^ a b Maisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD (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. PMID 1889806. 
  5. ^ 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. Bibcode:1995Natur.374..450A. doi:10.1038/374450a0. PMID 7700353. 
  6. ^ Huang EJ, Reichardt LF (2001). "Neurotrophins: Roles in Neuronal Development and Function". Annu. Rev. Neurosci. 24: 677–736. doi:10.1146/annurev.neuro.24.1.677. PMC 2758233. PMID 11520916. 
  7. ^ Yamada K, Nabeshima T (April 2003). "Brain-derived neurotrophic factor/TrkB signaling in memory processes". J. Pharmacol. Sci. 91 (4): 267–70. doi:10.1254/jphs.91.267. PMID 12719654. 
  8. ^ 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. Bibcode:2008PNAS..105.2711B. doi:10.1073/pnas.0711863105. PMC 2268201. PMID 18263738. 
  9. ^ 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:10.1006/mcne.1998.0684. PMID 9675054. 
  10. ^ Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA (1 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. 
  11. ^ Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (1 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. 
  12. ^ 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. 
  13. ^ "Phenotypes for BDNF homozygous null mice". Bdnf MGI Mouse Gene Detail - MGI:88145 - brain derived neurotrophic factor. Mouse Genome Informatics (MGI); The Jackson Laboratory. 
  14. ^ a b Pedersen BK (July 2013). "Muscle as a secretory organ". Compr Physiol 3 (3): 1337–62. doi:10.1002/cphy.c120033. PMID 23897689. 
  15. ^ Mandel AL, Ozdener H, Utermohlen V (July 2009). "Identification of Pro- and Mature Brain-derived Neurotrophic Factor in Human Saliva". Arch. Oral Biol. 54 (7): 689–95. doi:10.1016/j.archoralbio.2009.04.005. PMC 2716651. PMID 19467646. 
  16. ^ a b Patapoutian A, Reichardt LF (June 2001). "Trk receptors: mediators of neurotrophin action". Curr. Opin. Neurobiol. 11 (3): 272–80. doi:10.1016/S0959-4388(00)00208-7. PMID 11399424. 
  17. ^ 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:10.1523/JNEUROSCI.5378-07.2008. PMID 18495895. 
  18. ^ Costa MS, Botton PH, Mioranzza S, Ardais AP, Moreira JD, Souza DO, Porciúncula LO (September 2008). "Caffeine improves adult mice performance in the object recognition task and increases BDNF and TrkB independent on phospho-CREB immunocontent in the hippocampus". Neurochem. Int. 53 (3-4): 89–94. doi:10.1016/j.neuint.2008.06.006. PMID 18620014. 
  19. ^ Cotman CW, Berchtold NC (June 2002). "Exercise: a behavioral intervention to enhance brain health and plasticity". Trends Neurosci. 25 (6): 295–301. doi:10.1016/S0166-2236(02)02143-4. PMID 12086747. 
  20. ^ a b Bos I, De Boever P, Emmerechts J, Buekers J, Vanoirbeek J, Meeusen R, Van Poppel M, Nemery B, Nawrot T, Panis LI (August 2012). "Traffic related gene expression changes in mouse brain tissue.". Inhalation Toxicology 24 (10): 676–686. doi:10.3109/08958378.2012.714004. PMID 22906174. 
  21. ^ Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (2011). "Exercise training increases size of hippocampus and improves memory". Proc. Natl. Acad. Sci. U.S.A. 108 (7): 3017–22. doi:10.1073/pnas.1015950108. PMC 3041121. PMID 21282661. 
  22. ^ a b Vaynman S, Gomez-Pinilla F (September 2006). "Revenge of the "sit": how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity". J. Neurosci. Res. 84 (4): 699–715. doi:10.1002/jnr.20979. PMID 16862541. 
  23. ^ a b van Praag H, Christie BR, Sejnowski TJ, Gage FH (November 1999). "Running enhances neurogenesis, learning, and long-term potentiation in mice". Proc. Natl. Acad. Sci. U.S.A. 96 (23): 13427–31. Bibcode:1999PNAS...9613427V. doi:10.1073/pnas.96.23.13427. PMC 23964. PMID 10557337. 
  24. ^ Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA (March 2007). "An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus". Proc. Natl. Acad. Sci. U.S.A. 104 (13): 5638–43. Bibcode:2007PNAS..104.5638P. doi:10.1073/pnas.0611721104. PMC 1838482. PMID 17374720. 
  25. ^ Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR (November 2002). "Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity". J. Neurophysiol. 88 (5): 2187–95. doi:10.1152/jn.00152.2002. PMID 12424260. 
  26. ^ Martin B, Mattson MP, Maudsley S (2006). "Caloric restriction and intermittent fasting: two potential diets for successful brain aging". Ageing Res. Rev. 5 (3): 332–53. doi:10.1016/j.arr.2006.04.002. PMC 2622429. PMID 16899414. 
  27. ^ Mattson MP, Chan SL, Duan W (2002). "Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior". Physiol. Rev. 82 (3): 637–72. doi:10.1152/physrev.00004.2002. PMID 12087131. 
  28. ^ 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:10.1016/S0092-8674(03)00035-7. PMID 12553913. 
  29. ^ Bath KG, Lee FS (March 2006). "Variant BDNF (Val66Met) impact on brain structure and function". Cogn Affect Behav Neurosci 6 (1): 79–85. doi:10.3758/CABN.6.1.79. PMID 16869232. 
  30. ^ Terracciano A, Piras MG, Lobina M, Mulas A, Meirelles O, Sutin AR, Chan W, Sanna S, Uda M, Crisponi L, Schlessinger D (Dec 2013). "Genetics of serum BDNF: meta-analysis of the Val66Met and genome-wide association study.". The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 14 (8): 583–9. doi:10.3109/15622975.2011.616533. PMID 22047184. 
  31. ^ "Omim - Brain-Derived Neurotrophic Factor; BDNF". omim.org. Retrieved 2013-02-26. 
  32. ^ 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 (4): 306–310. doi:10.1002/ajmg.10133. PMID 11840487. 
  33. ^ Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity". Nat. Genet. 41 (1): 18–24. doi:10.1038/ng.274. PMID 19079260. 
  34. ^ Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, et al. (January 2009). "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nat. Genet. 41 (1): 25–34. doi:10.1038/ng.287. PMC 2695662. PMID 19079261. 
  35. ^ Dwivedi Y (2009). "Brain-derived neurotrophic factor: role in depression and suicide". Neuropsychiatr Dis Treat 5: 433–49. doi:10.2147/NDT.S5700. PMC 2732010. PMID 19721723. 
  36. ^ Brunoni AR, Lopes M, Fregni F (December 2008). "A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression". Int. J. Neuropsychopharmacol. 11 (8): 1169–80. doi:10.1017/S1461145708009309. PMID 18752720. 
  37. ^ Grande I, Fries GR, Kunz M, Kapczinski F (Dec 2010). "The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder". Psychiatry Investig. 2010 December; 7(4): 243–250. 7 (4): 243–50. doi:10.4306/pi.2010.7.4.243. PMC 3022310. PMID 21253407. 
  38. ^ Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL, Chen da C, Kosten TR, Zhang XY (August 2009). "Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics". Prog. Neuropsychopharmacol. Biol. Psychiatry 33 (8): 1508–12. doi:10.1016/j.pnpbp.2009.08.011. PMID 19720106. 
  39. ^ Maina G, Rosso G, Zanardini R, Bogetto F, Gennarelli M, Bocchio-Chiavetto L (August 2009). "Serum levels of brain-derived neurotrophic factor in drug-na?ve obsessive-compulsive patients: A case-control study". J Affect Disord 122 (1–2): 174–8. doi:10.1016/j.jad.2009.07.009. PMID 19664825. 
  40. ^ Zuccato C, Cattaneo E (June 2009). "Brain-derived neurotrophic factor in neurodegenerative diseases". Nature Reviews Neurology 5 (6): 311–22. doi:10.1038/nrneurol.2009.54. PMID 19498435. 
  41. ^ Zajac MS, Pang TY, Wong N, Weinrich B, Leang LS, Craig JM, Saffery R, Hannan AJ (June 2009). "Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington's disease mice". Hippocampus 20 (5): 621–36. doi:10.1002/hipo.20658. PMID 19499586. 
  42. ^ Zeev BB, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, Vecsler M, Vecksler M, Christodoulou J (April 2009). "The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome". Neurology 72 (14): 1242–7. doi:10.1212/01.wnl.0000345664.72220.6a. PMC 2677489. PMID 19349604. 
  43. ^ Arancio O, Chao MV (June 2007). "Neurotrophins, synaptic plasticity and dementia". Curr. Opin. Neurobiol. 17 (3): 325–30. doi:10.1016/j.conb.2007.03.013. PMID 17419049. 
  44. ^ Mercader JM, Fernández-Aranda F, Gratacòs M, Ribasés M, Badía A, Villarejo C, Solano R, González JR, Vallejo J, Estivill X (2007). "Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients". Neuropsychobiology 56 (4): 185–90. doi:10.1159/000120623. PMID 18337636. 
  45. ^ Kaplan AS, Levitan RD, Yilmaz Z, Davis C, Tharmalingam S, Kennedy JL (January 2008). "A DRD4/BDNF gene-gene interaction associated with maximum BMI in women with bulimia nervosa". Int J Eat Disord 41 (1): 22–8. doi:10.1002/eat.20474. PMID 17922530. 
  46. ^ Bos I, Jacobs L, Nawrot TS, de Geus B, Torfs R, Int Panis L, Degraeuwe B, Meeusen R (August 2011). "No exercise-induced increase in serum BDNF after cycling near a major traffic road.". Neuroscience Letters 500 (2): 129–132. doi:10.1016/j.neulet.2011.06.019. PMID 21708224. 
  47. ^ Bos I, De Boever P, Int Panis L, Sarre S, Meeusen R (October 2012). "Negative effects of ultrafine particle exposure during forced exercise on the expression of Brain-Derived Neurotrophic Factor in the hippocampus of rats". Neuroscience 223: 131–9. doi:10.1016/j.neuroscience.2012.07.057. PMID 22867973. 
  48. ^ Pareja-Galeano H, Sanchis-Gomar F, Mayero S (2013). "Autism spectrum disorders: possible implications of BDNF modulation through epigenetics". Acta Psychiatr Scand 128 (1): 97. doi:10.1111/acps.12071. PMID 23331212. 
  49. ^ Whiteley P. "The mixed up world of brain-derived neurotrophic factor and autism". Questioning Answers. News and views on autism research and other musings. 
  50. ^ Halepoto DM, Bashir S, A L-Ayadhi L (2014). "Possible role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder: current status". J Coll Physicians Surg Pak 24 (4): 274–8. PMID 24709243. 
  51. ^ Warner-Schmidt JL, Duman RS (2006). "Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment". Hippocampus 16 (3): 239–49. doi:10.1002/hipo.20156. PMID 16425236. 
  52. ^ 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:10.1016/S0306-4522(00)00349-3. PMID 11074154. 
  53. ^ Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, Li X (November 2006). "Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB". Brain Res. 1122 (1): 56–64. doi:10.1016/j.brainres.2006.09.009. PMID 17022948. 
  54. ^ Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M (July 2003). "Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants". Biol. Psychiatry 54 (1): 70–5. doi:10.1016/S0006-3223(03)00181-1. PMID 12842310. 
  55. ^ Okamoto T, Yoshimura R, Ikenouchi-Sugita A, Hori H, Umene-Nakano W, Inoue Y, Ueda N, Nakamura J (July 2008). "Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study". Prog. Neuropsychopharmacol. Biol. Psychiatry 32 (5): 1185–90. doi:10.1016/j.pnpbp.2008.02.009. PMID 18403081. 
  56. ^ Gorgulu Y, Caliyurt O (September 2009). "Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression". Brain Res. Bull. 80 (3): 158–62. doi:10.1016/j.brainresbull.2009.06.016. PMID 19576267. 
  57. ^ a b Drzyzga ŁR, Marcinowska A, Obuchowicz E (June 2009). "Antiapoptotic and neurotrophic effects of antidepressants: a review of clinical and experimental studies". Brain Res. Bull. 79 (5): 248–57. doi:10.1016/j.brainresbull.2009.03.009. PMID 19480984. 
  58. ^ Taylor SM (June 2008). "Electroconvulsive therapy, brain-derived neurotrophic factor, and possible neurorestorative benefit of the clinical application of electroconvulsive therapy". J ECT 24 (2): 160–5. doi:10.1097/YCT.0b013e3181571ad0. PMID 18580563. 
  59. ^ "'Blood chemicals link' to eczema". BBC News. 2007-08-26. 
  60. ^ 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. 
  61. ^ Tanaka T, Saito H, Matsuki N (1 May 1997). "Inhibition of GABAA synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus". J Neurosci 17 (9): 2959–66. PMID 9096132. 
  62. ^ Mattson MP (November 2008). "Glutamate and neurotrophic factors in neuronal plasticity and disease". Ann. N. Y. Acad. Sci. 1144: 97–112. Bibcode:2008NYASA1144...97M. doi:10.1196/annals.1418.005. PMC 2614307. PMID 19076369. 
  63. ^ Swardfager W, Herrmann N, Marzolini S, Saleem M, Shammi P, Oh PI, Albert PR, Daigle M, Kiss A, Lanctôt KL (August 2011). "Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease". Brain Behav. Immun. 25 (6): 1264–71. doi:10.1016/j.bbi.2011.04.017. PMID 21554945. 
  64. ^ Vargas-Perez H, Ting-A Kee R, Walton CH, Hansen DM, Razavi R, Clarke L, Bufalino MR, Allison DW, Steffensen SC, van der Kooy D (June 2009). "Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats". Science 324 (5935): 1732–4. Bibcode:2009Sci...324.1732V. doi:10.1126/science.1168501. PMC 2913611. PMID 19478142. 
  65. ^ Haniu M, Montestruque S, Bures EJ, Talvenheimo J, Toso R, Lewis-Sandy S, Welcher AA, Rohde MF (October 1997). "Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking". J. Biol. Chem. 272 (40): 25296–303. doi:10.1074/jbc.272.40.25296. PMID 9312147. 
  66. ^ Naylor RL, Robertson AG, Allen SJ, Sessions RB, Clarke AR, Mason GG, Burston JJ, Tyler SJ, Wilcock GK, Dawbarn D (March 2002). "A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4". Biochem. Biophys. Res. Commun. 291 (3): 501–7. doi:10.1006/bbrc.2002.6468. PMID 11855816. 
  67. ^ Fatemi SH (2008). Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease. Berlin: Springer. pp. 444 pages. ISBN 978-0-387-76760-4. ; see the chapter "A Tale of Two Genes: Reelin and BDNF"; pp. 237-245
  68. ^ 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. doi:10.1016/S0896-6273(00)80540-1. PMID 9728912. 

Further reading[edit]

External links[edit]