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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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