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Relationship: 448

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

BDNF, Reduced leads to Synaptogenesis, Decreased

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment non-adjacent Moderate Low Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Mixed High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
During brain development High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Disruption of BDNF signaling (and other factors, such as NGF or Reelin, etc.) during brain development was shown to interfere with synaptogenesis in the hippocampus (Sanchez-Martin et al., 2013; Neal et al., 2010; Stansfiled et al., 2012). In the adult brain, BDNF is involved in synaptic plasticity (Lu et al., 2013; Leal et al., 2014), which is a fundamental process linked with learning and memory. Synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease, and synaptic repair therapies based on the use of trophic factors, such as BDNF, are currently under consideration (Lu et al., 2013).

BDNF is released by the BDNF-producing neurons of the CNS and binds to Trk-B of the PV-interneurons, an interaction necessary for the subsequent developmental effects of this neurotrophin (Polleux et al., 2002; Jin et al., 2003; Rico et al., 2002; Aguado et al., 2003). BDNF promotes the morphological and neurochemical maturation of hippocampal and neocortical interneurons and promotes GABAergic synaptogenesis (Danglot et al., 2006; Hu and Russek, 2008).

BDNF plays an important role in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development (Chapleau et al., 2009). Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, as well as in mouse models of these disorders (Chapleau et al., 2009).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

BDNF, in addition to its pro-survival effects, has powerful synaptic effects, promoting synaptic transmission, synaptic plasticity and synaptogenesis (Lu et al., 2013; Sanchez-Martin et al., 2013; Neal et al., 2010; Stansfiled et al., 2012; Danglot et al., 2006; Hu and Russek, 2008). NMDAR activity has been linked to the signaling of the trans-synaptic neurotorophin BDNF (Neal et al., 2010).

Use of selective agonist or antagonist of BDNF receptor TrkB demonstrates the contribution of BDNF in synaptogenesis in adult-generated neurons in the rat dentate gyrus (Ambrogini et al., 2013). In this regard, exogenous application of BDNF significantly increased the number of functional synapses in culture (Vicario-Abejon et al., 1998; Marty et al., 2000), while blocking of BDNF with antibodies greatly reduced the formation of inhibitory synapses (Seil and Drake-Baumann, 2000). Similar results were described also in an in vivo study on mutant mice characterized by deletion of the trkB gene in cerebellar precursors (obtained by Wnt1-driven Cre--mediated recombination). TrkB mutant mice showed reduced amounts of GABAergic markers and develop reduced numbers of GABAergic boutons and synaptic specializations, whilst granule and Purkinje cell dendrites appeared normal and the former presented typical numbers of excitatory synapses. This study demonstrated that TrkB is essential to the development of GABAergic neurons and the regulation of synapse formation (Rico et al., 2002). BDNF is also a potent regulator of spontaneous neuronal activity in GABAergic neurons and interneurons, as shown in in embryonic (E18) hippocampal slices (Aguado et al., 2003), and plays a critical role in controlling the emergence, complexity and networking properties of spontaneous networks.

TH deficiency during the foetal and/or the neonatal period, apart from reducing synaptogenesis, can produce several other deleterious effects for neural growth and development (e.g., such as reduced synaptic connectivity, delayed myelination, disturbed neuronal migration, deranged axonal projections, and alterations in neurotransmitters' levels), possibly through decreased BDNF levels (Koromilas et al., 2010; Shafiee et al., 2016).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Alterations of BDNF signaling is probably not the only mechanism leading to impaired synaptogenesis and synaptic plasticity. Indeed NMDAR activity can also modulate nitric oxide (NO) signaling. Exogenous NO addition during Pb exposure results in complete recovery of whole-cell synaptophysin levels and partial recovery of synaptophysin and synaptobrevin in synapses in Pb-exposed neurons (Neal et al., 2012). In addition, in Wistar rats, the anti-oxidant and radical scavenger quercetin was able to relieve the impairment of synaptic plasticity induced by chronic Pb exposure (from parturition through adulthood (PND 60); 0.2% Pb in drinking water of mothers and post-weaning pups) (Hu et al., 2008), suggesting that oxidative stress can also interfere with synapse formation.

Additionally, while PTU (a TPO inhibitor) has been shown to decrease brain BDNF levels and expression in offspring born from PTU-treated rat dams (Shafiee et al. 2016; Chakraborty et al., 2012; Gilbert et al. 2016), in the study from Cortés and colleagues (Cortés et al., 2012), treatment of adult male Sprague-Dawley rats with PTU induced an increase in the amount of BDNF mRNA in the hippocampus, while the content of TrkB protein, the BDNF receptor, resulted reduced at the PSD of the CA3 region compared with controls. Treated rats presented also thinner PSD than control rats, and a reduced content of NMDAr subunits (NR1 and NR2A/B subunits) at the PSD. These indicate differential effects elicited by PTU (i.e., TPO inhibition) on BDNF expression/regulation comparing the adult vs foetal brain. However, even though BDNF levels were increased, the decrease of BDNF receptor (TrkB) compromises the signalling pathway under BDNF control.

Results variability from study to study is due to different experimental study designs, accounting for differences in brain development stages (PND vs adult), times of exposures to chemicals, and regional brain differences.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Empirical evidence comes from work with laboratory rodent-derived cells and brain slices, and rodent in vivo studies.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Aguado F, Carmona MA, Pozas E, Aguiló A, Martínez-Guijarro FJ, Alcantara S, Borrell V, Yuste R, Ibañez CF, SorianoE. (2003). BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl–co-transporter KCC2. Development 130:1267-1280.

Ambrogini P, Lattanzi D, Ciuffoli S, Betti M, Fanelli M, Cuppini R. (2013). Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF. Brain Res 1534: 1-12.

Buckmaster PS, Ingram EA, Wen X. (2009). Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. Jun 24; 29(25):8259-69.

Chakraborty G, Magagna-Poveda A, Parratt C, Umans JG, MacLusky NJ, Scharfman HE. (2012). Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU). Endocrinology 153:1311–1316.

Chapleau CA, Larimore JL, Theibert A, Pozzo-Miller L. (2009). Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. J Neurodev Disord;1:185–196.

Chen WH, Wang M, Yu SS, Su L, Zhu DM, She JQ, et al. (2007). Clioquinol and vitamin B12 (cobalamin) synergistically rescue the lead-induced impairments of synaptic plasticity in hippocampal dentate gyrus area of the anesthetized rats in vivo. Neuroscience 147(3): 853-864.

Cortés C, Eugenin E, Aliaga E, Carreño LJ, Bueno SM, Gonzalez PA, Gayol S, Naranjo D, Noches V, Marassi MP, Rosenthal D, Jadue C, Ibarra P, Keitel C, Wohllk N, Court F, Kalergis AM, Riedel CA. (2012). Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density. Thyroid. Sep;22(9):951-63.

Danglot L, Triller A, Marty S. (2006). The development of hippocampal interneurons in rodents. Hippocampus. 16:1032-1060.

Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology, Feb;157(2):774-87

Hu Y, Russek SJ. (2008). BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 105:1-17.

Hu P, Wang M, Chen WH, Liu J, Chen L, Yin ST, et al. (2008). Quercetin relieves chronic lead exposure-induced impairment of synaptic plasticity in rat dentate gyrus in vivo. Naunyn Schmiedebergs Arch Pharmacol. Jul;378(1):43-51.

Jin X, Hu H, Mathers PH, Agmon A. (2003). Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures. J Neurosci 23:5662–5673.

Koibuchi N, Yamaoka S, Chin WW. (2001). Effect of altered thyroid status on neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11:205–210.

Koromilas C, Liapi C, Schulpis KH, Kalafatakis K, Zarros A, Tsakiris S. Structural and functional alterations in the hippocampus due to hypothyroidism. Metab Brain Dis. 2010 Sep;25(3):339-54.

Leal G, Comprido D, Duarte CB. (2014). BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76 Pt C: 639-656.

Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. (2013). BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14(6): 401-416.

Marty S, Wehrle R, Sotelo C. (2000). Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus. J Neurosci 20: 8087–8095.

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(1): 249-263.

Neal AP, Stansfield KH, Guilarte TR. (2012). Enhanced nitric oxide production during lead (Pb(2)(+)) exposure recovers protein expression but not presynaptic localization of synaptic proteins in developing hippocampal neurons. Brain Res 1439: 88-95.

Polleux F, Whitford KL, Dijkhuizen PA, Vitalis T, Ghosh A. (2002). Control of cortical interneuron migration by neurotrophins and PI3-kinase signaling. Development 129:3147–60.

Rico B, Xu B, Reichardt LF. (2002). TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233.

Sanchez-Martin FJ, Fan Y, Lindquist DM, Xia Y, Puga A. (2013). Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells. PLoS One 8(11): e80558.

Sato K, Akaishi T, Matsuki N, Ohno Y, Nakazawa K. (2007). beta-Estradiol induces synaptogenesis in the hippocampus by enhancing brain-derived neurotrophic factor release from dentate gyrus granule cells. Brain Res. May 30;1150:108-20.

Schildt S, Endres T, Lessmann V, Edelmann E. (2013). Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus. Neuropharmacology. Aug;71:247-54.

Schjetnan AG, Escobar ML. (2012). In vivo BDNF modulation of hippocampal mossy fiber plasticity induced by high frequency stimulation. Hippocampus. Jan;22(1):1-8.

Seil FJ, Drake-Baumann R. (2000). TrkB receptor ligands promote activity-dependent inhibitory synaptogenesis. J Neurosci 20: 5367–73.

Shafiee SM, Vafaei AA, Rashidy-Pour A. (2016). Effects of maternal hypothyroidism during pregnancy on learning, memory and hippocampal BDNF in rat pups: Beneficial effects of exercise. Neuroscience. Aug 4;329:151-61.

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(1): 277-295.

Vicario-Abejon C, Collin C, McKay RD, Segal M. (1998). Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J Neurosci 18:7256–71

Westerholz S, de Lima AD, Voigt T. (2013). Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Front Cell Neurosci 7:121.

Xiao Y, Fu H, Han X, Hu X, Gu H, Chen Y, et al. (2014). Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats. PLoS One 9(12): e115556.