Decreased, Neuronal network function in adult brain leads to Impairment, Learning and memory

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.

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Quantitative evaluation of this KER does not exist.

Administration of DomA (9.0 mg DomA kg(-1) bw, i.p.) to Sparus aurata (seabream) caused neurological disturbances such as swimming in a circle, in a spiral, or upside down, that were reversed 24 hours after exposure (Nogueira et al., 2010). In rainbow trout (Oncorhynchus mykiss), DomA (0.75 mg/kg bw) administration caused increased aggressive behaviour 30 min after exposure compared to controls (Bakke et al., 2010).