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Decreased, Neuronal network function in adult brain 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|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||adjacent||Moderate||Low||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
It is well established in the existing literature that NMDA receptor–dependent synaptic potentiation (LTP) and depression (LTD) are two forms of activity directly linked to long-term changes in synaptic efficacy and plasticity, the fundamental processes underlying learning and memory. The best characterized form of LTP occurs in the CA3-CA1 region of the hippocampus, in which LTP is initiated by transient activation of NMDARs that leads to a persistent increase in synaptic transmission through AMPA receptors (Benke et al., 1998) that can be achieved either through increasing the number of AMPA receptors at the post-synaptic surface or by increasing the single channel conductance of the receptors expressed. It has been shown that LTP in the CA1 region of the hippocampus could be accounted for by these two mechanisms (Benke et al 1998). The degree of activity of NMDARs is determined in part by extracellular Mg(2+) and by the co-agonists for this receptor, glycine and D-serine. During strong stimulation, a relief of the voltage-dependent block of NMDARs by Mg(2+) provides a positive feedback for NMDAR Ca(2+) influx into postsynaptic CA1 spines. The induction of LTP at CA3-CA1 synapses requires further signal amplification of NMDAR activity. Src family kinases (SFKs) play a "core" role in the induction of LTP by enhancing the function and expression of NMDARs. At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity. Many transmitters and signal pathways can modify NMDAR function and expression and, for a given stimulus strength, they can potentially lead to a change in the balance between LTP and LTD (MacDonald et al., 2006).
Mammalian learning and memory is one of the outcomes of the functional expression of neurons connected into neural networks. Neuronal damage or cell death induced by chemical compounds disrupts integration and transmission of information through neural networks thereby setting the stage for subsequent impairment of learning and memory. Exposure to chemicals that will increase the risk of functional neuronal network damage lead to learning and memory impairment.
Evidence Supporting this KER
Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy after high-frequency stimulation of afferent fibers, and its discovery potentiated the idea that individual synapses possess the properties expected for learning and memory (reviewed in Lynch et al., 2014). Moreover, LTP is intimately related to the theta rhythm, an oscillation long-associated with learning. Learning-induced enhancement in neuronal excitability, a measurement of neural network function, has also been shown in hippocampal neurons following classical conditioning in several experimental approaches (reviewed in Saar and Barkai, 2003). On the other hand, memory requires the increase in magnitude of EPSCs to be developed quickly and to be persistent for a at least a few weeks without disturbing already potentiated contacts. Once again, a substantial body of evidence have demonstrated that tight connection between LTP and diverse instances of memory exist (reviewed in Lynch et al., 2014).
The recent studies suggest that NMDA receptor-dependent long-term depression of both LTD and LTP is usually accompanied by morphological changes in spines. LTD is characterized by long lasting dendritic spine shrinkage and reduced F-actin polymerization, in addition to reduced numbers of synaptic AMPA receptors. Moreover, the actin binding protein cofilin has been implicated in mediating such synaptic structural plasticity (Chen et al., 2007). If sustained, such LTD-changes in hippocampus or cortex, triggered by NMDARs overactivation could lead to synaptic dysfunction, contributing to learning and memory damage (Calabrese et al., 2014).
Uncertainties and Inconsistencies
One of the most difficult issues for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is still unclear exactly what modifications in neuronal circuits need to happen in order to alter motor behaviour as it is recorded in a learning and memory test (Mayford et al., 2012), meaning that there is no clear understanding about how these two KEs are connected.
It is unclear whether GLF affects only glutamatergic systems since other potential mechanisms underlying GLF neurotoxicity have not been widely investigated. Based on the existing data it is understood that exposure to GLF or NAcGLF could disrupt the neuronal network function through disruption of glutamatergic neurotransmission but further work is required to clarify molecular mechanisms that cause impairment of memory.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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