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BDNF, Reduced leads to Impairment, Learning and memory
Key Event Relationship Overview
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||Arthur Author (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||Moderate|
Key Event Relationship Description
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
Evidence Supporting this KER
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
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Empirical evidence comes from in vivo studies with rodents.
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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.