API

Relationship: 1507

Title

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BDNF, Reduced leads to Impairment, Learning and memory

Upstream event

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BDNF, Reduced

Downstream event

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Impairment, Learning and memory

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment non-adjacent Moderate Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

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Sex Evidence
Unspecific Moderate

Life Stage Applicability

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Term Evidence
During brain development Moderate

Key Event Relationship Description

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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 Supporting this KER

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Biological Plausibility

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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).

Empirical Evidence

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Some studies have shown associations between decrease of BDNF (e.g., as a consequence of exposure to several pollutants, such as BPA) and reduction of memory and learning:

- Wang et al., 2016: in this in vivo study, pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on PND 21 with the object recognition task. Data revealed a decrease in BDNF (~ 38% decrease at 50 mg/kg BW/day vs control) in the hippocampus. BPA-exposed male offspring underwent memory and cognitive impairments: they not only spent more time (~ 43% more, at 1.5 hr after training) in exploring the familiar object at the highest dose than the control, but also displayed a significant decrease in the object recognition index (at 50 mg/kg BW/day, ~ 54% lower short term memory measured 1.5 hr after training).

- Jang et al., 2012: In this in vivo study, pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were analysed. Exposure of F0 mice to BPA (10 mg/kg) decreased hippocampal neurogenesis (~ 30% decrease of hippocampal BrdU+ cells vs control) in F2 female mice. High-dose BPA (10 mg/kg) caused neurocognitive deficit (i.e., reduced memory retention) as shown by passive avoidance testing (~ 33% decrease vs control) in F2 mice. Furthermore, 10 mg/kg BPA decreased the hippocampal levels of BDNF (~ 35% lower vs control) in F2 mice. These results suggest that BPA exposure (causing inhibition of NIS function) in pregnant mothers could decrease hippocampal neurogenesis and cognitive function in future generations.

- Shafiee et al., 2016 This in vivo study investigated the effects of PTU (TPO inhibitor, 100 mg/L) in pregnant rats to evaluate the effects elicited by maternal hypothyroidism in the offspring. PTU was added to the drinking water from gestation day 6 to PND 21. Analysis of hippocampal BDNF levels, and learning and memory tests were performed on PNDs 45-52 on pups. These results indicated that hypothyroidism during the fetal period and the early postnatal period was associated with: (i) ~ 70% reduction of total serum T4, (ii) ~ 5-fold increase of total serum TSH levels (on PND 21; no significant differences could be found at the end of the behavioral testing, on PND 52), (iii) reduction of hippocampal BDNF protein levels (~ 8% decrease vs control), (iv) impairment of spatial learning and memory, in both male and female rat offspring.

- Gilbert and Sui, 2006, Gilbert, 2011, Gilbert et al., 2016: (in vivo studies) Long-term potentiation (LTP) is a model of activity-dependent synaptic plasticity critical for learning and memory. LTP is impaired in both sub-regions of hippocampus under conditions of TH deficiency, and these impairments persist in the adult offspring on recovery of euthyroid status. LTP induces activation of neurotrophins, particularly BDNF and related signaling molecules. Induction of these pathways underlies the persistence of experience-dependent plasticity. Offspring of hypothyroid animals are deficient in LTP and in the induction of neurotrophin gene changes in response to neuronal activation. Similar plasticity is operative during early brain development, influencing synapse formation and formation of neural networks.

- Gilbert et al., 2016: in this in vivo study, exposure to PTU during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. Developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes in neonate hippocampus (e.g., at PND14, rats treated with 3 ppm PTU, underwent reduction of Bdnft by ~25%, Bdnfiv by ~10%, Ngf by ~25%, and Pval by ~50%) and was accompanied by deficits in hippocampal-based learning (e.g., mean latency to find a hidden platform, at 2nd trial resulted ~60% higher in rats treated with 10 ppm PTU).

- Liu et al., 2010: This in vivo study assessed the effects of hypothyroidism in 60 female rats who were divided into three groups: (i) maternal subclinical hypothyroidism (total thyroidectomy with T4 infusion), (ii) maternal hypothyroidism (total thyroidectomy without T4 infusion), and (iii) control (sham operated). Data showed that rat pups born from subclinical hypothyroidism dams had lower BDNF mRNA expression (on PND 3) and protein level (on PND 3 and PND 7) in the hippocampus. Moreover, the Morris water maze tests revealed that pups from the subclinical hypothyroidism group showed long-term memory deficits, and a trend toward short-term memory deficits.

- Wang et al., 2012: This in vivo study showed that maternal subclinical hypothyroidism impairs spatial learning in the offspring, as well as the efficacy and optimal time of T4 treatment in pregnancy. Female adult Wistar rats were randomly divided into six groups: control, hypothyroid (H), subclinical hypothyroid (SCH) and SCH treated with T4, starting from GD10, GD13 and GD17, respectively, to restore normal TH levels. Results indicate that progenies of both SCH and H groups had lower levels of BDNF protein (~35% lower in both groups) and also of Egr1, Arc, and p-ERK compared to controls. T4 treatment ameliorated these protein expression changes in the progeny of rats with subclinical hypothyroidism. Moreover, the SCH and H groups demonstrated significantly longer mean latency in the water maze test (on the 2nd training day, latency was ~83% higher in H group, and ~50% higher in SCH), and a lower amplification percentage of the amplitude (~15% lower in H group, and 12% lower in SCH), and slope of the field excitatory postsynaptic potential (fEPSP) recording (~20% lower in H group, and 17% lower in SCH), compared to control group. T4 treatment at GD10 and GD13 significantly shortened mean latency and increased the amplification percentage of the amplitude and slope of the fEPSPs of the progeny of rats with subclinical hypothyroidism. However, T4 treatment at GD17 showed only minimal effects on spatial learning in the offspring. Altogether these data indicate direct correlation between decrease of BDNF and learning and memory deficits.

- Bekinschtein et al. 2008: in this in vivo study, the protein synthesis inhibitor anisomycin (Ani; 80 μg/0.8 μl per side) was injected in the dorsal hippocampus of Male Wistar rats (2.5 months) 12 h after inhibitory avoidance (IA) training (i.e., using a strong foot shock, which generates a persistent LTM), which causes a selective deficit in memory retention 7 days, but not 2 days, after training. Human recombinant BDNF (hrBDNF, 0.25 μg/0.8 μl per side) or vehicle (Veh) was delivered 15 min after Ani infusion into the hippocampus. hrBDNF completely rescued long-term memories (LTM) at 7 days after training caused by Ani given at 12 h after training. Additionally, infusion of BDNF antisense oligonucleotides (i.e., BDNF ASO, which blocks the expression of BDNF 12 h after training) into the dorsal hippocampus 10 h after training, was found to impair persistence (a characteristic feature of LTM), but not formation of IA LTM (as compared with BDNF missense oligonucleotide). This indicates that BDNF during the late posttraining critical time period is not only required but sufficient for persistence of LTM storage. This study also supports essentiality of this KE (i.e., decreased BDNF).

- Alonso et al. 2002: in this in vivo study the role of BDNF in both short and long term memories (STM and LTM) formation of a hippocampal-dependent one-trial fear-motivated learning task was examined in male Wistar rats (2–3 months). IA training was found associated with a rapid and transient increase in BDNF mRNA expression (by 90%, 1 hr after IA training) in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody (0.5 µg/side) into the CA1 region of the dorsal hippocampus decreased ERK2 activation, and blocked STM formation. On the contrary, intrahippocampal administration of rhBDNF (0.25 µg/side) increased ERK1/2 activation and facilitated STM. These results strongly indicate that endogenous BDNF is required for both STM and LTM formation of an IA learning. This study also supports essentiality of this KE (i.e., decreased BDNF).

- Blanco et al. 2013: in this in vivo study rat dams were exposed to 0, 1 and 2 mg/kg/day of BDE-99 from GD 6 to PND 21. Data showed that transmission of maternal accumulated BDE-99 through placenta and breast milk caused a decrease of serum levels of T3 (by 13 ± 9% in the 2 mg/kg/day group), T4 (by 25 ± 13% in the 2 mg/kg/day group) and a decrease of free-T4 (by up to 17 ± 9% in the 2 mg/kg/day group), causing downregulation of BDNF gene expression in the hippocampus of pups (by 32 ± 14% in the 2 mg/kg/day group). Moreover, BDE-99 produced a delay in the spatial learning task in the water maze test (i.e., longer latency in reaching the platform at the highest BDE-99 dose vs control group), and a dose-response anxiolytic effect as revealed by the open-field test.

Uncertainties and Inconsistencies

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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.

Quantitative Understanding of the Linkage

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Despite some studies reporting strong associations between decrease of BDNF and learning and memory deficits (e.g., Liu et al., 2010; Wang et al., 2012; Shafiee et al., 2016), it is still not defined how much decrease in BDNF release is needed to observe learning and memory impairment. This highlights the need to produce empirical data based models for this KER.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Empirical evidence comes from in vivo studies with rodents.

References

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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.

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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.

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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.

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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.