To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:381

Event: 381

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Reduced levels of BDNF

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
BDNF, Reduced

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Molecular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
neural cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
gene expression brain-derived neurotrophic factor decreased
secretion brain-derived neurotrophic factor decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Binding of antagonist to NMDARs impairs cognition KeyEvent Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed
NIS inhibition and learning and memory impairment KeyEvent Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed
Binding of antagonist to NMDARs can lead to neuroinflammation and neurodegeneration KeyEvent Florianne Tschudi-Monnet (send email) Open for citation & comment WPHA/WNT Endorsed

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
During brain development High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

BDNF (Brain-derived neurotrophic factor) plays a critical role in normal brain development in most vertebrates, primarily documented empirically in mammalian species. Klein et al. (2011) examined blood, serum, plasma and brain-tissue and measured BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method (Aid et al., 2007), whereas Trajkovska et al. 2007 determined BDNF levels in human blood.

There is compelling data that demonstrates the role  of  BDNF  in brain development for many other taxa, including fish where it acts as neurotrophic factor in controlling cell proliferation (D'Angelo L et al., 2014; Heinrich and Pagtakhan, 2004) and  birds where BDNF influences development of the brain area that involved in the song control (Brenowitz 2013) and  the addition of new neurons to a cortical nucleus in adults . In the Xenopus visual system, BDNF acts as neurotrophic factor that mediates synaptic differentiation and maturation of the retinotectal circuit through cell autonomous tropomycin receptor kinase B also known as tyrosine receptor kinase B (TrkB) signaling on retinal ganglion cells (Sanchez et al., 2006; Marshak et al., 2007).

Biological state: BDNF belongs to a family of closely related neurotrophic factors named neurotrophins and is widely expressed in the developing and mature central nervous system (CNS). In the rodent cortex, postnatal BDNF expression is initially low but slowly increases to reach high levels around weaning. Therefore, BDNF expression peaks at a time when both structural and functional maturation of cortical circuitry occurs. During postnatal development, BDNF levels are dynamically regulated, in part by neuronal activity dependent mechanisms (Waterhouse and Xu, 2009). Glutamate has been shown to increase the transcription and release of BDNF. Indeed, BDNF is synthesized, stored and released from glutamatergic neurons (Lessmann et al., 2003).

Biological compartments: BDNF initially is synthesized as precursor proteins (proBDNF), which is processed intracellularly to be transformed in its mature form (mBDNF) after proteolytically cleaved in the synaptic cleft by plasmin which is a protease activated by tissue plasminogen activator (tPA) (Cohen-Cory et al., 2010). proBDNF is constantly secreted while tPA release and mBDNF production depends on neuronal excitation (Head et al., 2009). Storage and activity-dependent release of BDNF has been demonstrated in both dendrites and axon terminals (Waterhouse and Xu, 2009). More specifically, in hippocampus, BDNF appears to be stored in dendritic processes of neurons (Balkowiec and Katz, 2002). BDNF is abundant in cerebellum and cortex and has also been measured in cerebrospinal fluid (CSF) (Zhang et al., 2008), whole blood, plasma, serum (plasma without clotting factors) and platelets (Trajkovska et al., 2007). BDNF has been found to be produced by astrocytes under both physiological and pathological conditions (Endo, 2005; Coco et al., 2013; Nelson and Alkon, 2014).

In humans (Pruunsild et al., 2007), mBDNF is sequestered in platelets, consequently BDNF can reach all tissues and organs. Lymphocytic cells have been shown to express BDNF in vitro similarly to eosinophils, dendritic cells, and endothelial cells. The visceral and airway epithelium are also significant sources of BDNF. Female reproductive system including ovaries, placenta and uterus also express BDNF (Wessels et al., 2014).

General role in biology: The biological functions of mBDNF are mediated by binding to tyrosine kinase B (TrkB) receptor that leads to the activation of three major intracellular signalling pathways, including MAPK, PI3K and PLCγ1 (Soulé et al., 2006). TrkB-mediated signaling regulates gene transcription in the nucleus through the activation of several transcription factors. These genes are involved in neurite outgrowth, synaptogenesis, synapse maturation and stabilization (Pang et al., 2004; Lu et al., 2005; Nelson and Alkon, 2014).

On the other hand, proBDNF binds to the p75 neurotrophin receptor (p75NTR) and activates RhoA, a small GTPase that regulates actin cytoskeleton polymerization leading to inhibition of axonal elongation, growth cone collapse, and apoptosis (Dubreuil et al., 2003; Yamauchi et al., 2004; Head et al., 2009).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

No OECD methods are available to measure BDNF protein and mRNA levels. Measuring BDNF levels changes in the brain, especially when low, at the boarder to be significant are technically difficult. Depending on the tissue or fluid measurements distinct methods are used.

Brain tissue: BDNF protein levels can be measured by commercial available antibody sandwich ELISA kits, Western blotting, immunohistochemistry and immunofluorescence. BDNF primers for different exons are available to determine mRNA levels by RT-PCR. The Bdnf gene consists of multiple alternative exons (ten in human, eight in rodents and six in lower vertebrates), and a single exon coding for the entire pro-BDNF protein (Cohen-Cory et al., 2010).

Cerebro-spinal fluid (CSF): There are available commercial antibody sandwich ELISA kits (Trajkovska et al., 2007) and immunobead-based multiplex assays for high throughput screening (Zhang et al., 2008).

Whole blood, serum, plasma and platelets: There are several commercial double antibody sandwich ELISA kits that can be used for identification of BDNF levels in biological fluids (Trajkovska et al., 2007).

Methodological considerations that have to be taken into account during sample preparation and measurement of BDNF by ELISA have been recently reviewed in Elfving et al. 2010. A study measuring BDNF by a commercially available ELISA kit in various tissues and biological liquids derived from distinct species revealed that BDNF is undetectable in mouse blood and pig plasma (Klein et al., 2011). This study also showed that in most cases BDNF levels are comparable to levels reported in humans and that there is positive correlation between blood BDNF levels and hippocampal BDNF levels in rats and pigs (Klein et al., 2011).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

BDNF plays a critical role in normal brain development in most vertebrates, primarily documented empirically in mammalian species. Klein et al. (2011) examined blood, serum, plasma and brain-tissue and measured BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method (Aid et al., 2007), whereas Trajkovska et al. 2007 determined BDNF levels in human blood.

There is compelling data that demonstrates the role  of  BDNF  in brain development for many other taxa, including fish where it acts as neurotrophic factor in controlling cell proliferation (D'Angelo L et al., 2014; Heinrich and Pagtakhan, 2004) and  birds where BDNF influences development of the brain area that involved in the song control (Brenowitz 2013) and  the addition of new neurons to a cortical nucleus in adults . In the Xenopus visual system, BDNF acts as neurotrophic factor that mediates synaptic differentiation and maturation of the retinotectal circuit through cell autonomous TrkB signaling on retinal ganglion cells (Sanchez et al., 2006; Marshak et al., 2007).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T. (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res. 85: 525-535.

Balkowiec A, Katz DM. (2002) Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci. 22: 10399-10407.

Brenowitz EA. (2013) Testosterone and brain-derived neurotrophic factor interactions in the avian song control system. Neuroscience 239: 115-123.

Coco M, Caggia S, Musumeci G, Perciavalle V, Graziano AC, Pannuzzo G, Cardile V. (2013) Sodium L-lactate differently affects brain-derived neurothrophic factor, inducible nitric oxide synthase, and heat shock protein 70 kDa production in human astrocytes and SH-SY5Y cultures.J Neurosci Res. 91: 313-320.

Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S. (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol. 70: 271-288.

D'Angelo L, De Girolamo P, Lucini C, Terzibasi ET, Baumgart M, Castaldo L, Cellerino A (2014). Brain-derived neurotrophic factor: mRNA expression and protein distribution in the brain of the teleost Nothobranchius furzeri. J Comp Neurol. 1;522(5):1004-30.

Dubreuil CI, Winton MJ, McKerracher L. (2003) Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J Cell Biol. 162: 233-243.

Elfving B, Plougmann PH, Wegener G. (2010) Detection of brain-derived neurotrophic factor (BDNF) in rat blood and brain preparations using ELISA: pitfalls and solutions. J Neurosci Methods 187: 73-77.

Endo T. (2005) Glycans and glycan-binding proteins in brain: galectin-1-induced expression of neurotrophic factors in astrocytes. Curr Drug Targets. 6:427-436.

Head BP, Patel HH, Niesman IR, Drummond JC, Roth DM, Patel PM. (2009) Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 110: 813-825.

Heinrich G, Pagtakhan CJ. (2004) Both 5' and 3' flanks regulate Zebrafish brain-derived neurotrophic factor gene expression. BMC Neurosci. 5: 19.

Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S. (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol. 14: 347-353.

Lessmann V, Gottmann K, Malcangio M. (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. 69: 341-374.

Lu B, Pang PT, Woo NH. (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci. 6: 603-614.

Marshak S, Nikolakopoulou AM, Dirks R, Martens GJ, Cohen-Cory S (2007)Cell-autonomous TrkB signaling in presynaptic retinal ganglion cells mediates axon arbor growth and synapse maturation during the establishment of retinotectal synaptic connectivity. J Neurosci 27:2444 –2456.

Nelson TJ, Alkon DL. (2014) Molecular regulation of synaptogenesis during associative learning and memory. Brain Res. pii: S0006-8993(14)01660-6. doi: 10.1016/j.brainres.2014.11.054.

Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B. (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 306: 487-491.

Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T. (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics. 90: 397-406.

Sanchez AL, Matthews BJ, Meynard MM, Hu B, Javed S, Cohen Cory S (2006) BDNF increases synapse density in dendrites of developing tectal neurons in vivo. Development 133:2477–2486.

Soulé J, Messaoudi E, Bramham CR. (2006) Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans. 34 :600-604.

Trajkovska V, Marcussen AB, Vinberg M, Hartvig P, Aznar S, Knudsen GM. (2007) Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Res Bull. 73: 143-149.

Waterhouse EG, Xu B. (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 42: 81-89.

Wessels JM, Wu L, Leyland NA, Wang H, Foster WG. (2014) The Brain-Uterus Connection: Brain Derived Neurotrophic Factor (BDNF) and Its Receptor (Ntrk2) Are Conserved in the Mammalian Uterus. PLoS ONE 9: e94036.

Yamauchi J, Chan JR, Shooter EM. (2004) Neurotrophins regulate Schwann cell migration by activating divergent signaling pathways dependent on Rho GTPases. Proc Natl Acad Sci U S A. 101: 8774-8779.

Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, Chung KA, Millard SP, Nutt JG, Montine TJ. (2008) CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol. 129: 526-529.