Upstream eventDecreased, Neuronal network function in adult brain
Impairment, Learning and memory
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||non-adjacent||Moderate||Low|
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).
Include consideration of temporal concordance here
A series of important findings support that the biochemical changes that happen after induction of LTP also occur during memory acquisition, showing temporality between the two KEs (reviewed in Lynch et al., 2014). Furthermore, a review of Morris water maze (MWM)data as a tool to investigate spatial learning and memory in laboratory rats also pointed to the disconnection between neuronal networks rather than brain damage of certain regions is responsible for the impairment of MWM performance(D'Hooge and De Deyn, 2001). Functional integrated neural networks that involve the coordination action of different brain regions are consequently important for spatial learning and MWM performance. Morris et al. 1986 found that blocking the NMDA receptor with AP5 inhibits spatial learning in rats. More importantly, in the same study they measured brain electrical activity and recorded that this agent also inhibits LTP, however, they did not prove that spatial learning and LTP inhibition are causally related (Morris et al., 1986). Since then a number of NMDA receptor antagonists have been studied for their ability to induce impairment of learning and memory. It is worth mentioning that similar findings have been found in human subjects, where by combining behavioural and electrophysiological data from patients with temporal lobe epilepsy exposed to ketamine, the involvement of NMDA receptors in human memory processes was demonstrated (Grunwald et al., 1999).
Domoic Acid (DomA): Mice exposed to DomA (2.0 mg/kg) showed impairment of the acquisition of the place task in the Morris water maze (Petrie et al., 1992). These animals also failed to select the appropriate problem-solving strategies in their attempt to search for the underwater platform (longer escape latencies than controls) (Petrie et al., 1992). This impairment of acquisition and retention of this spatial navigation task by DomA, was associated with neuronal damage not only in the hippocampus, but also in limbic brain regions (Petrie et al., 1992). Similar results were obtained in a different study that also utilized the Morris water maze but in rats (Kuhlmann and Guilarte, 1997). These animals received DomA (1.5 or 3.0 mg/kg i.p.) and exhibited significant learning deficits while animals treated with a lower dose (0.75 mg/kg) showed no deficits. By incorporating in the test a visual cue trial (a black flag was positioned over the goal platform to eliminate the learning and memory components), it was possible to rule out sensory and motor deficits in the treated animals unable to solve the task (Kuhlmann and Guilarte, 1997).
Rats were examined using a neurobehavioral test battery (passive avoidance, auditory startle and conditioned avoidance) after DomA treatment with 0, 0.22, 0.65, or 1.32 mg/kg i.p. that caused hardly any measurable brain injury (Sobotka et al., 1996). Approximately 25% of the animals that received the higher dose (1.32 mg/kg) DomA died or were euthanized. Surviving animals were assessed three days after exposure and showed changes on the auditory startle test (Sobotka et al., 1996). This effect was limited to exaggerated startle responses as measured by mean-response amplitude changes and did not include changes in habituation, suggesting the presence of behavioural hyper-reactivity rather than memory impairment. No change on the other two measures of avoidance learning was detected for all DomA treated groups compared to controls (Sobotka et al., 1996).
In an experimental approach aiming to evaluate single versus repeated doses of DomA on learning and memory, adult mice were treated with single or four i.p. injections of 1.0 or 2.0 mg/kg over a seven day period. All animals were tested on a spatial delayed matching-to-sample test in Morris water maze (Clayton et al., 1999). Animals given a single dose of 2.0 mg/kg DomA performed more poorly than controls on “nonalternation” test days; sessions in which the correct response was the same as the preceding day (Clayton et al., 1999). This finding implies that DomA-treated animals had difficulty recalling information after a 24 h delay period and were exhibiting behavioural signs similar to human antegrade amnesia. Animals exposed to multiple doses displayed initially greater general symptomatology but after recovery, did not show greater cognitive impairment than subjects treated with a single injection (Clayton et al., 1999).
In the only study where DomA i.v. administration was tested in relation to impairment of learning and memory, rats were dosed with 0.04 μg DomA/kg (and diazepam, ip). Radial arm maze tests revealed severe learning impairment, suggesting deficits in working memory. In subjects that were able to ultimately solve the maze, performance deficits were documented on re-learning the same task. The memory-based deficits observed in these animals are similar to human antegrade amnesia that has been reported after DomA exposure (Nakajima and Potvin, 1992). In humans, the hallmark of DomA-induced neurotoxicity is the rather dramatic disruption of memory processing. Clinical evaluation of 14 adult human subjects poisoned by DomA (after the outbreak in Canada) revealed that the majority of them (12/14) had severe antegrade memory deficits with relative preservation of higher cortical functions, since the patients were unable to remember events that occurred after DomA intoxication and had difficulty recalling new information (reviewed in Pulido, 2008; Grant et al., 2010).
In a separate clinical report of one case, a patient that received treatment at the hospital for DomA poisoning showed memory impairment which was resolved after three weeks (reviewed in Pulido, 2008; Grant et al., 2010). Other symptoms of the syndrome include nausea, vomiting, abdominal cramps, diarrhoea, headache, unstable blood pressure, cardiac arrhythmias and neurological dysfunction, including coma and seizures (reviewed in Pulido, 2008; Grant et al., 2010).
Treatment of female Sprague-Dawley rats with 0, 1, 2, 4, or 7.5 mg domoic acid/kg of body weight for 24 h caused neurobehavioural changes at doses above 4 mg/kg of body weight characterised by unequivocal behavioural and neurological signs leading to partial seizures and status epilepticus(Tryphonas et al., 1990).Similar effects were observed in other in vivio studies ( Fuquay et al., 2012; Muha and Ramsdell, 2011).
The exposed zebrafish from the 36-week treatment with DomA showed no visible signs of neurobehavioral excitotoxicity (i.e.circle- or spiral-swimming) when observed over a 30–45 min period following each injection (Hiolski et al., 2014). The latencies measured during training sessions did not differ among treated and not treated animals but the step-through latency in the 24 h retention trial was significantly lowered in DomA-exposed mice (2 mg/kg once a day for 3 weeks) (Lu et al., 2012). DomA-treated mice had longer escape latencies compared to controls in Morris water maze. The same group reported that DomA-treated mice (2 mg/kg once a day for 3 weeks)compared to controls showed a decrease (4.5 fold) in the step-through latency in the 24 h retention trial, a decrease (4 fold) in the number of crossings over the exact former location of the platform and a reduction (3 fold) in the time spent in the target quadrant (where the platform was located during hidden platform training) during the MWM task probe test (Wu et al., 2013, Wu et al, 2012). In this study FoxO1 knockdown reversed the cognitive deficits induced by DA in mice (Wu et al., 2013).
Adult male and female Sprague Dawley rats received a single intraperitoneal injection of DomA (0, 1.0, 1.8 mg/kg). These low levels of DomA showed that males may be more susceptible to severe neurotoxicity, whereas females are affected more quickly as it increased locomotor and grooming activity after monitoring behaviour for 3h (Baron et al., 2013).
1. GLF impairs neuronal network function. The networks of cortical rat neurons were exposed to glufosinate (GLF) and its primary metabolite N-acetylglufosinate (NAcGLF) and electrical activity was measured using microelectrode array (MEA). The MEA recordings showed the concentration-responses for GLF and NAcGLF on network mean firing rates (MFR) that were biphasic, increasing at lower concentrations, decreasing below control levels at higher concentrations (similarly to NMDA). Increases in MFR occurred between 100–300 uM for NAcGLF (190% control, maximum) and 10–1000 uM for GLF (340% control, maximum) indicating that GLF is affecting neuronal network function (Lantz et al., 2014). Toxicokinetic data from reports of intentional human poisonings indicate that GLF concentrations in the CNS could reach levels high enough to lead to effects mediated via NMDARs (Watanabe and Sano, 1998).
Direct activation of NMDARs by GLF is also suggested by in vivo studies where three NMDA receptor antagonists, dizocilpine, LY235959, and Compound 40, and AMPA/KA antagonist, NBQX, were co-administrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the GLF-induced convulsions, while the AMPA/KA receptor antagonist had no effect. These results suggest that the convulsion caused by glufosinate ammonium were mediated through NMDA receptors (Matsumura et al., 2001).
2. GLF exposure triggers convulsions and memory impairment. GLF expsoure produces moderate to severe convulsions and memory loss (Koyama et al., 1994; Watanabe and Sano, 1998; Ohtake et al., 2001; Park et al., 2006, 2013; Mao et al., 2011a and b, 2012), as well as causes structural changes to several brain regions, including the cortex and hippocampus (Calas et al., 2008; Meme et al., 2009; Park et al., 2006 ), two brain structures rich in NMDARs that play an important role in learning and memory processes.
• A 64 year old patient who ingested GLF suffered mental disturbances and later developed generalized convulsions, impaired respiration and circulatory failure. During recovery he exhibited loss of short-term memory (retrograde and anterograde amnesia) (Watanabe and Sano, 1998).
• Similarly, a 34-yr-old man who ingested glufosinate ammonium developed mental deterioration (Park et al., 2013).
• Retrograde amnesia has been reported following acute GLF toxicity in humans (Park et al., 2006).
• Chronic GLA (glufosinate-ammonium) treatments with 5 and 10mg/kg induce mild memory impairments and a modification of hippocampal texture in mice. It is suggested that these modifications may be causally linked one to another. Hippocampal MRI texture and spatial memory alterations might be the consequences of hippocampal glutamate homeostasis modification (Calas et al., 2008).
• Spatial memory impairment was observed in mice after chronic exposure to as low as 2.5 mg/kg of GLF (Calas et al.,2008; Meme et al., 2009).
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.
Quantitative Understanding of the Linkage
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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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).
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