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Relationship: 1507

Title

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 Impairment, Learning and memory

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
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment non-adjacent Moderate Moderate 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
Term Scientific Term Evidence Link
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During brain development Moderate

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

BDNF and its high-affinity receptor TrkB are widely expressed in the mammalian brain (Lewin and Barde, 1996). They play a crucial role in the development, maintenance and functioning of the CNS (Huang and Reichardt, 2003; Shafiee et al., 2016). BDNF is known to be directly regulated by thyroid hormones and plays essential roles during the critical period of fetal brain development (Wang et al., 2006), including cell proliferation, migration, differentiation, synaptogenesis and neuronal network formation. In addition, neuronal activity regulates BDNF transcription, transport of BDNF mRNA and protein into dendrites and the activity-dependent secretion of BDNF, which, in turn, modulate synaptic plasticity, synaptogenesis and memory formation (Bekinschtein et al., 2008).

Developmental thyroid hormone insufficiency is associated with reduced cognitive functions and lowered BDNF levels, as shown in both humans and animal models (Chakraborty et al., 2012). For instance, in rats, maternal thyroidectomy significantly reduces BDNF expression in the brain of developing pups (Liu et al., 2010), leading to learning and memory deficits. Prenatal exposure to PTU also leads to reduced hippocampal BDNF in neonatal rats (Chakraborty et al., 2012). This evidence supports the link between decrease of BDNF and learning and memory impairment described in this indirect KER.

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

The BDNF gene is a key signal transduction element required for synaptic plasticity and many forms of associative learning (Lu et al., 2005; Park et al., 2013). Moreover, reduced function of BDNF leads to neurodevelopmental and learning disorders (Bienvenu et al., 2006). 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).

BDNF protein is synthesized as a precursor (pre-proBDNF), resulting after cleavage in a 32-kDa proBDNF protein. ProBDNF is either proteolytically cleaved intracellularly by enzymes like furin or pro-convertases and secreted as the 14 kDa mature BDNF (mBDNF), or secreted as proBDNF and then cleaved by extracellular proteases, such as metalloproteinases and plasmin, to mBDNF (see Lessmann et al., 2003). Both proBDNF and mBDNF are preferentially sorted and packaged into vesicles of the activity-regulated secretory pathway. ProBDNF is not an inactive precursor of BDNF; it is released in the immature and mature CNS in an activity dependent manner (for a comprehensive review on the role of BDNF in learning and memory, see Cunha et al. 2010). The intracellular localization of BDNF is predominantly somatodendritic, but it is also enriched in the dendrites. BDNF can activate several signalling pathways (e.g., ERK (Orban et al., 1999; Sweatt, 2004; Thomas and Huganir, 2004), PI3K–Akt (Lin et al., 2001), CREB (Barco et al., 2003)) that may regulate downstream cellular effects necessary for synaptic plasticity and memory formation. The role of BDNF in synaptogenesis and neuronal network functions, which represent the KEs before the AO (decrease of learning and memory), was already described in other three AOPs (i.e., 13, 48 and 12) already endorsed by OECD.

Importantly, reduced levels of BDNF have been reported as a consequence of decreased TH levels, playing a crucial role in neuroplasticity, one of the fundamental processes in learning and memory (Chakraborty et al., 2012; Gilbert and Lasley, 2013). In line with this, BDNF-mediated stimulation of both hippocampal neurogenesis and inhibition of hippocampal apoptosis can recover spatial memory deficits triggered by developmental hypothyroidism in rats (Shafiee et al., 2016; Shin et al., 2013).

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

There are no inconsistencies in this KER; however, alterations of BDNF signalling is reliably not the only mechanism leading to impaired learning and memory. Additional studies are required to better correlate BDNF levels, TH brain levels with learning and memory tests performed simultaneously.

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
Time-scale
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

Empirical evidence comes from in vivo studies with rodents.

References

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

Alonso M, Vianna MR, Depino AM, Mello e Souza T, Pereira P, Szapiro G, Viola H, Pitossi F, Izquierdo I, Medina JH (2002). BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus. 12(4):551-60.

Barco A, Pittenger C, Kandel ER (2003). CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets. Feb; 7(1):101-14.

Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008). BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A. Feb 19;105(7):2711-6.

Bienvenu T, Chelly J. (2006). Molecular genetics of Rett syndrome: When DNA methylation goes unrecognized. Nat. Rev. Genet; 7:415–426.

Blanco J, Mulero M, Heredia L, Pujol A, Domingo JL, Sánchez DJ (2013). Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring. Toxicology. Jun 7;308:122-8.

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.

Cunha C, Brambilla R, Thomas KL (2010). A simple role for BDNF in learning and memory? Front Mol Neurosci. Feb 9;3:1.

Gilbert ME. (2011). Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci 124:432-445.

Gilbert ME, Lasley SM (2013). Developmental thyroid hormone insufficiency and brain development: a role for brain-derived neurotrophic factor (BDNF)? Neuroscience, 239, pp. 253-270.

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 157:774-787.

Gilbert ME, Sui L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.

Huang EJ, Reichardt LF. (2003). Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem, 72, pp. 609–642.

Jang YJ, Park HR, Kim TH, Yang WJ, Lee JJ, Choi SY, Oh SB, Lee E, Park JH, Kim HP, Kim HS, Lee J. (2012). High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations. Toxicology. Jun 14;296(1-3):73-82.

Lessmann V, Gottmann K, Malcangio M (2003). Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. Apr; 69(5):341-74.

Lewin GR, Barde YA. (1996) Physiology of the neurotrophins. Annu Rev Neurosci, 19, pp. 289–317.

Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Chang WC, Gean PW (2001). A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron. Sep 13; 31(5):841-51.

Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H. (2010). The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid 20:909–915.

Lu B, Pang TP, Woo NH (2005). The Yin and Yang of neurotrophin action. Nat. Rev. Neurosci. 2005;6:603–614.

Orban PC, Chapman PF, Brambilla R (1999). Is the Ras-MAPK signalling pathway necessary for long-term memory formation? Trends Neurosci. Jan; 22(1):38-44.

Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. (2013). Nat. Rev. Neurosci;14:7–23.

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.

Shin MS, Ko IG, Kim SE, Kim BK, Kim TS, Lee SH, Hwang DS, Kim CJ, Park JK, Lim BV (2013). Treadmill exercise ameliorates symptoms of methimazole-induced hypothyroidism through enhancing neurogenesis and suppressing apoptosis in the hippocampus of rat pups. Int J Dev Neurosci. May;31(3):214-23.

Sweatt JD (2004). Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol. Jun; 14(3):311-7.

Thomas GM, Huganir RL (2004). MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. Mar; 5(3):173-83.

Wang Y, Su B, Xia Z. (2006). Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. J Biol Chem, 281, pp. 35965–35974.

Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848.

Wang C, Li Z, Han H, Luo G, Zhou B, Wang S, Wang J. (2016). Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus. Toxicology. Feb 3;341-343:56-64.