Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

Magdalini Sachana, Sharon Munn and Anna Bal-Price
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Magdalini Sachana: Joint Research Centre, European Commission, Ispra
Sharon Munn: Joint Research Centre, European Commission, Ispra
Anna Bal-Price: Joint Research Centre, European Commission, Ispra

No 5, OECD Series on Adverse Outcome Pathways from OECD Publishing

Abstract: It is well documented and accepted that learning and memory processes rely on physiological functioning of the glutamate receptor N-methyl-D-aspartate (NMDAR). Both animal and human studies investigating NMDA itself, experiments with NMDAR antagonists and mutant mice lacking NMDAR subunits strongly support this statement (Rezvani, 2006). Activation of NMDARs results in long-term potentiation (LTP), which is related to increased synaptic strength, plasticity and memory formation in the hippocampus (Johnston et al., 2009). LTP induced by activation of NMDA receptors has been found to be elevated in the developing rodent brain compared to the mature brain, partially due to 'developmental switch' of the NMDAR 2A and 2B subunits (Johnston et al., 2009). Activation of the NMDAR also enhances brain derived neurotrophic factor (BDNF) release, which promotes neuronal survival, differentiation and synaptogenesis (Tyler et al., 2002; Johnston et al., 2009). Consequently, the blockage of NMDAR by chemical substances during synaptogenesis disrupts neuronal network formation resulting in the impairment of learning and memory processes (Toscano and Guilarte, 2005). This AOP is relevant to developmental neurotoxicity (DNT). The molecular initiating event (MIE) is described as the chronic binding of antagonist to NMDAR in neurons during synaptogenesis (development) in hippocampus (one of the critical brain structures for learning and memory formation). One of the chemicals that blocks NMDAR after chronic exposure is lead (Pb2+), a well-known developmental neurotoxicant.

Keywords: developmental neurotoxicity; impairment of learning and memory; N-methyl-D-aspartate receptor (NMDAR) (search for similar items in EconPapers)
Date: 2016-08-13
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