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Event: 1335

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Reduced, BDNF (Brain-derived neurotrophic factor)

Short name

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Reduced, BDNF

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neural cell

Organ term

Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). 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 signaling 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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

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
Network of SSRIs	KeyEvent	Lyle Burgoon (send email)	Open for adoption
Mental stress to depression	KeyEvent	Lyle Burgoon (send email)	Open for adoption
Mental stress to agitation	KeyEvent	Lyle Burgoon (send email)	Open for adoption
Binding of Alpha 1-Adrenergics to Antagonists Leading to Depression	KeyEvent	LUANA GOMES (send email)	Under development: Not open for comment. Do not cite

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 KE.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

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

Life stage	Evidence
During brain development	High

Sex Applicability

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

Term	Evidence
Unspecific	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. More help

The brain-derived neurotrophic factor (BDNF) is synthesized and secreted by excitatory neurons. It is a key regulator involved in synaptic plasticity and fundamental brain processes such as cognition and memory (Barde, 2025).
BDNF belongs to the neurotrophin family and is present throughout the central nervous system (CNS), both during development and in the mature brain. Experiments conducted with rodents have shown that postnatal expression in the prefrontal cortex is low and gradually increases as the brain matures. Therefore, it becomes evident that BDNF levels reach maturity in parallel with the maturation of cortical brain areas (Cohen-Cory et al., 2010).
The first step in the entire process involving this neurotrophin is its synthesis and secretion. Both its expression and synthesis depend on tightly regulated mechanisms, which primarily reflect the regulation of its gene. This mechanism is essential to ensure the availability and functional activity of BDNF in specific cellular locations (Tongiorgi et al., 2006).
The BDNF gene consists of alternatively organized exons, and its structure varies among species. For example, there are ten exons in humans, eight in rodents, and six in lower vertebrates, with only a single exon capable of fully encoding the pro-BDNF protein. The expression of the BDNF gene can be controlled by different types of promoters, which function independently depending on development, tissue type, and cellular activity. Moreover, the organization of the BDNF gene is highly conserved between fish and mammals (Aid et al., 2007; Tao et al., 2002; Rattiner et al., 2004; Kidane et al., 2009; Heirinch et al., 2004; Pruunsild et al., 2007).
BDNF secretion occurs through two pathways: constitutive and regulated. Constitutive secretion mainly occurs in the soma, while the regulated pathway predominates in distal neuronal processes. Efficient targeting of BDNF to the regulated secretory pathway depends primarily on a specific region within the pro-domain of BDNF (Brigadiski et al., 2005).
The following diagram illustrates the general process of activation, regulation of synthesis, and secretion of BDNF at pre- and postsynaptic sites. Presynaptic activity induces the activation of postsynaptic NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Locally produced BDNF mRNA is transported to the dendritic spine, where it is translated into protein and directed to the postsynaptic site in an activity-dependent manner. This BDNF binds to presynaptic TrkB receptors, activating intracellular signaling pathways that influence the activity of the GTPases RhoA, Rac, and Cdc42, which in turn modify actin structure through the cytoskeleton. Rac and Cdc42 act as positive regulators of cell growth and also play essential roles in neuronal branching. Additionally, BDNF can act in an autocrine manner through the activation of postsynaptic TrkB receptors (Cory et al., 2011).
Scientific evidence shows that BDNF activation through its TrkB receptor can promote the morphological development of neurons and is also associated with synaptic connectivity (Huang & Reichardt et al., 2001; Poo et al., 2001; Zweifel et al., 2005).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

BDNF can be measured in human serum using the enzyme-linked immunosorbent assay (ELISA) technique. (Naegelin et al; 2018);
To measure or detect BDNF, various methods can be employed, including molecular biology techniques, immunohistochemistry, and other approaches such as immunohistochemical staining, quantitative real-time polymerase chain reaction (qPCR), and Western blot analysis (Ding et al., 2017);
Commercially available kits utilizing sandwich enzyme-linked immunosorbent assay (ELISA) techniques have been developed to detect BDNF in cerebrospinal fluid using specific antibodies. Moreover, multiplex immunobead-based assays are employed for high-throughput and targeted screening of BDNF levels. (Trajkvska et al, 2007; Zhang et al., 2008);
In the commercial market, a variety of assay kits are available for detecting and quantifying BDNF levels in different biological fluids, including whole blood, plasma, and platelets. (Trajkovska et al., 2007).
Certain precautions should be considered when measuring or detecting BDNF in plasma or serum using the ELISA method. A specific study that measured BDNF concentrations in mouse and porcine serum reported that BDNF was undetectable using this methodological approach. (Elfving et al., 2010; Klein et al., 2011)

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Brain-derived neurotrophic factor (BDNF) is associated with essential and fundamental brain processes in most vertebrates. Its empirical relationship with mammals has been well documented. Previous studies have investigated the determination of BDNF in whole blood, serum, plasma, and brain tissue. In one of these studies, BDNF concentrations were measured in three different mammalian species — rat, pig, and mouse — using the ELISA method. As mentioned earlier, other research groups have also demonstrated the quantification of BDNF in human serum. (Klein et al., 2011; Aid et al., 2007; Trajkovska et al. 2007).
The role of BDNF can be observed in the brain development of fish, where it regulates cell proliferation; in birds, where it is involved in specific brain regions controlling song production; and in the visual system of Xenopus, where BDNF functions as a neurotrophic factor mediating synaptic differentiation. (Sanchez et al., 2006; Marshak et al., 2007; Brenowitz, 2013; D'Angelo L et al., 2014; Heinrich e Pagtakhan, 2004).

References

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

Aid, T., Kazantseva, A., Piirsoo, M., Palm, K. and Timmusk, T. (2007). Revisiting the structure and expression of the BDNF gene in mice and rats. Journal of Neuroscience Research, 85(3): 525–535. DOI: 10.1002/jnr.21139. PMID: 17149751. PMCID: PMC1878509.

Barde YA (2024). A fisiopatologia do fator neurotrófico derivado do cérebro. Revisões Fisiológicas. DOI:10.1152/physrev.00038.2024

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

Brigadski, T., Hartmann, M. and Lessmann, V. (2005). Differential vesicular targeting and time course of synaptic secretion of the mammalian neurotrophins. Journal of Neuroscience, 25(33): 7601–7614. PMID: 16107647. PMCID: PMC6725410.

Cohen-Cory, S., Kidane, AH, Shirkey, NJ, & Marshak, S. (2010). Fator neurotrófico derivado do cérebro e o desenvolvimento da conectividade neuronal estrutural . Neurobiologia do Desenvolvimento, 70 (5), 271–288. https://doi.org/10.1002/dneu.20774

Cowan, W. M., Jessell, T. M. and Zipursky, S. L. (2001). Neurotrophins as synaptic modulators. Nature Reviews Neuroscience, 2(1): 24–32. DOI: 10.1038/35049004. PMID: 11253356.

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.

Ding, S., T. Zhu, Y. Tian, P. Xu, Z. Chen, X. Huang and X. M. Zhang (2017), Role of brain-derived neurotrophic factor in endometriosis pain, Reproductive Sciences, https://doi.org/10.1177/1933719117732161

Elfving B, Plougmann PH, Wegener G. (2010) Detecção do fator neurotrófico derivado do cérebro (BDNF) em sangue de rato e preparações cerebrais usando ELISA: dificuldades e soluções. J Neurosci Methods 187: 73-77.

Heinrich, G. and Pagtakhan, C. J. (2004). Both 5′ and 3′ flanks regulate zebrafish brain-derived neurotrophic factor gene expression. BMC Neuroscience, 5: 19. DOI: 10.1186/1471-2202-5-19. PMID: 15153250. PMCID: PMC442124.

Huang and Reichardt (2001) – Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24: 677–736. PMID: 11520916. PMCID: PMC2758233.

Kidane, A. H., Heinrich, G., Dirks, R. P. H., de Ruyck, B. A., Lubsen, N. H., Roubos, E. W. and Jenks, B. G. (2009). Differential neuroendocrine expression of multiple brain-derived neurotrophic factor transcripts. Endocrinology, 150(4): 1361–1371. DOI: 10.1210/en.2008-0993. PMID: 19008311.

Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S. (2011) As concentrações de BDNF no sangue refletem os níveis de BDNF no tecido cerebral em diferentes espécies. Int J Neuropsychopharmacol. 14: 347-353.

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.

Naegelin, Y., H. Dingsdale, K. Säuberli, S. Schädelin, L. Kappos and Y.-A. Barde (2018), Measurement and validation of brain-derived neurotrophic factor (BDNF) levels in human serum, eNeuro, Vol. 5, No. 2, Article ENEURO.0419-17.2018, https://doi.org/10.1523/ENEURO.0419-17.2018

Pruunsild et al. (2007) – Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters. Gene 394(1–2): 1–13. PMID: 17629449. PMCID: PMC2568880.

Rattiner, L. M., Davis, M., French, C. T. and Ressler, K. J. (2004). Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. Journal of Neuroscience, 24(20): 4796–4806. DOI: 10.1523/JNEUROSCI.5654-03.2004. PMID: 15152040. PMCID: PMC6729469.

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.

Tongiorgi, E., Domenici, L. e Simonato, M. (2006). Qual é o significado biológico do direcionamento do mRNA do BDNF nos dendritos? Indícios da epilepsia e do desenvolvimento cortical. Neurobiologia Molecular , 33(1), 17–32. DOI: 10.1385/MN:33:1:017

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.

Xu, T., West, A. E., Chen, W. G., Corfas, G. and Greenberg, M. E. (2001). A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron, 33(3): 383–395. DOI: 10.1016/S0896-6273(01)00561-X. PMID: 11832226.

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.

Zweifel, L. S., Kuruvilla, R. and Ginty, D. D. (2005). Functions and mechanisms of retrograde neurotrophin signalling. Nature Reviews Neuroscience, 6(8): 615–625. DOI: 10.1038/nrn1727. PMID: 16062170.