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BDNF, Reduced leads to Aberrant, Dendritic morphology
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||adjacent||High||Low||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
The dendritically synthesized BDNF when secreted activates tyrosine kinase B (TrkB) receptors that induce the synthesis of a number of proteins involved in the development of proper dendritic spine morphology.
Evidence Supporting this KER
After activation of tyrosine kinase B (TrkB) receptors by BDNF proteins such as Arc, Homer2, LIMK1 (Kang and Schuman, 1996, Schratt et al., 2004 and Yin et al., 2002) that are known to promote actin polymerization and consequently enlargement of spine heads (Sala et al., 2001) are released. Recently, it has been shown that BDNF promotes dendritic spine formation by interacting with Wnt signaling. Indeed, Wnt signaling inhibition in cultured cortical neurons caused disruption in dendritic spine development, reduction in dendritic arbor size and complexity and blockage of BDNF-induced dendritic spine formation and maturation (Hiester et al., 2013).
In addition, it has been shown that the inhibition of BDNF synthesis reduces the size of spine heads and impairs LTP (An et al., 2008; Waterhouse and Xu, 2009). BDNF has been characterized as a critical factor in promoting dendritic morphogenesis in various types of neurons (reviewed in Jan and Jan, 2010; Park and Poo, 2013).
BDNF that is synthesised in dendrites is known to regulate the morphology of spines (Tyler and Pozzo-Miller, 2003; An et al., 2008). For example, spines in the absence of spontaneous electrical activity are significantly smaller than normal (Harvey et al., 2008). On the other hand, simultaneous electrical activity and glutamate release increase the size of the spine head, which has been shown to be dependent on BDNF (Tanaka et al., 2008).
Mice harboring the Val66Met mutation of Bdnf gene show dendritic arborization defects in the hippocampus. Interestingly, human subjects with the Val66Met SNP demonstrate similar anatomical features (reviewed in Cohen and Greenberg, 2008).
More targeted studies have shown that, within the physiological range of expression, dendritic spine density is tightly regulated by BDNF in the dentate gyrus but not in CA1 pyramidal cells (Alexis and Stranahan, 2011).
Uncertainties and Inconsistencies
Various molecular mechanisms have been identified as regulators of dendritic arborisation patterns and dendtitic spine formation (Jan and Jan, 2010). More specific, transcription factors, growth factors, receptor-ligand interactions, various signalling pathways, local translational machinery, cytoskeletal elements, Golgi outposts and endosomes have been identified as contributors to the organization of dendrites of individual neurons and the contribution of these dendrites in the neuronal circuitry (Jan and Jan, 2010). This study suggests that more parameters rather than only BDNF may be involved in dendritic arbor and spine formation during development.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
In organotypic slice cultures derived from the ferret visual cortex application of exogenous BDNF increased the length and complexity especially of Layer IV pyramidal neurons (McAllister et al., 1995) that was also activity-dependent (McAllister et al., 1996). Several studies conducted in rodents further support that the in vitro treatment of hippocampal cultures with exogenous BDNF increases dendritic growth in developing neurons (reviewed in Zagrebelsky and Korte, 2014).
Alexis M, Stranahan AM. (2011) Physiological variability in brain-derived neurotrophic factor expression predicts dendritic spine density in the mouse dentate gyrus. Neurosci Lett. 495: 60-62.
Alfano DP, Petit TL. (1982) Neonatal lead exposure alters the dendritic development of hippocampal dentate granule cells. Exp Neurol. 75: 275-288.
An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B, Xu B. (2008) Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134: 175-187.
Baek DH, Park SH, Park JH, Choi Y, Park KD, Kang JW, Choi KS, Kim HS. (2011) Embryotoxicity of lead (II) acetate and aroclor 1254 using a new end point of the embryonic stem cell test. Int J Toxicol. 30: 498-509.
Baranowska-Bosiacka I, Strużyńska L, Gutowska I, Machalińska A, Kolasa A, Kłos P, Czapski GA, Kurzawski M, Prokopowicz A, Marchlewicz M, Safranow K, Machaliński B, Wiszniewska B, Chlubek D. (2013) Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus. Toxicology 303: 187-200.
Cohen S, Greenberg ME. (2008) Communication between the synapse and the nucleus in neuronal development, plasticity and disease. Annu Rev Cell Dev Biol. 24: 183-209.
Harvey CD, Yasuda R, Zhong H, Svoboda K. (2008) The spread of Ras activity triggered by activation of a single dendritic spine. Science. 321: 136-140.
Hiester BG, Galati DF, Salinas PC, Jones KR. (2013) Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. Mol Cell Neurosci. 56: 115-127.
Hu F, Xu L, Liu Z-H, Ge M-M, Ruan D-Y, et al. (2014) Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro. PLoS ONE 9(7): e101894.
Huang F, Schneider JS. (2004) Effects of lead exposure on proliferation and differentiation of neural stem cells derived from different regions of embryonic rat brain. Neurotoxicology 25: 1001–1012.
Jan YN, Jan LY (2010). Branching out: mechanisms of dendritic arborization. Nat Rev Neurosci. 11: 316-328.
Kang H, Schuman EM. (1996) A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273: 1402-1406.
Kwon M, Fernández JR, Zegarek GF, Lo SB, Firestein BL. (2011) BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin. J Neurosci. 31: 9735-9745.
McAllister AK, Lo DC, Katz LC. (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15: 791-803.
McAllister AK, Katz LC, Lo DC. (1996) Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17: 1057-1064.
Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. (2010) Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicol Sci. 116: 249-263.
Park H, Poo MM. (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14: 7-23.
Sala C, Piech V, Wilson NR, Passafaro M, Liu G, Sheng M. (2001) Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31: 115-130.
Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME. (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci. 24: 7366-7377.
Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci. 127: 277-295.
Tanaka JI, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GCR, Kasai H. (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines Science 319: 1683-1687.
Tyler WJ, Pozzo-Miller L. (2003) Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones. J Physiol 553: 497-509.
Verina T, Rohde CA, Guilarte TR. (2007). Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neuroscience 145: 1037-1047.
Waterhouse EG, Xu B. (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 42: 81-89.
Yin Y, Edelman GM, Vanderklish PW. (2002) The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci USA. 99: 2368-2373.
Zagrebelsky M, Korte M. (2014) Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology. 76 PtC: 628-638.