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Relationship: 348


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

BDNF, Reduced leads to Aberrant, Dendritic morphology

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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).


List of the literature that was cited for this KER description. More help

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.