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Disruption, neurotransmitter release 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|
|Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release||adjacent||Not Specified||Not Specified||Travis Karschnik (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Neurotransmitters and their receptors are essential for brain functioning, learning, and memory. Catecholamines, including dopamine and norepinephrine, are the main neurotransmitters that mediate a variety of central nervous system (CNS) functions, such as motor control, cognition, emotion, memory processing, and endocrine modulation, determined by recent molecular genetic approaches in mice (Handra et al., 2019).
Evidence Collection Strategy
This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOPs "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release" and "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.
Evidence Supporting this KER
The N-methyl-D-aspartate receptor (NMDAR) plays an essential role in hippocampus-mediated learning and memory, based on studies showing that intra-ventricular administration of an NMDAR antagonist (aminophosphonovaleric acid (APV)) in rats resulted in spatial learning impairments similar to those encountered with hippocampal lesions (Morris et al., 1982; Morris et al., 1986).
Memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Short-term changes may include LTP and LTD whereas long-term morphological alterations may involve synaptogenesis and neuropil growth (Burns and Augustine 1995; Edwards 1995). Since BDNF significantly modulates both forms of synaptic changes and the expression is upregulated during memory acquisition, as described above, it may play a role in learning and memory (Lo DC 1995; Thoenen 1995; McAllister et al., 1999).
Cortical acetylcholine release increases (1) during acquisition but not during recall of a rewarded operant behavior (Orsetti et al., 1996), (2) during acquisition of operant tasks when demands on attentional processing are high (Muir et al., 1996), (3) during conditioned taste aversion (Miranda et al., 2003), and (4) during performance of visual attentional tasks (Himmelheber et al., 2001). It has been also related to attentional effort (Himmelheber et al., 2001). Furthermore, in the hippocampus, ACh release increases during the performance of a learned spatial memory task (Ragozzino et al., 1996; Stancampiano R, et al., 1999) and the increase is positively correlated to performance improvement during task learning (Fadda et al., 2000), showing that cholinergic neurons are modified functionally during learning and become progressively more active. Also, the initial use of a place strategy coincided with an immediate increase in hippocampus ACh release (Chang and Gold 2003). Furthermore, as rewarded spontaneous alternation testing progressed, a switch to a repetitive response strategy accompanied an increase in striatum ACh release (Pych JC et al., 2005).
The release of acetylcholine in different brain areas appears to be involved in processes of attention (Marrosu et al., 1995), detection of novelty or saliency (Baxter et al., 1999), and during the consolidation of different types of long-term memory (Power 2004; McIntyre et al., 2003; Hasselmo 1999).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
A. Toumane, T. Durkin, A. Marighetto, D. Galey, R. Jaffard Differential hippocampal and cortical cholinergic activation during the acquisition, retention, reversal and extinction of a spatial discrimination in an 8-arm radial maze by mice Behavioural Brain Research, 30 (1988), pp. 225-234
Ann E. Power, Almira Vazdarjanova, James L. McGaugh, Muscarinic cholinergic influences in memory consolidation, Neurobiology of Learning and Memory, Volume 80, Issue 3, 2003, Pages 178-193, ISSN 1074-7427
Baxter MG, et al. Impairments in conditioned stimulus processing and conditioned responding after combined selective removal of hippocampal and neocortical cholinergic input. Behav Neurosci. 1999;113:486.
Burns ME, Augustine GJ. Synaptic structure and function: dynamic organization yields architectural precision. Cell 1995; 83: 187–94.
Chang Q, Gold PE. Switching memory systems during learning: changes in patterns of brain acetylcholine release in the hippocampus and striatum in rats. J Neurosci. 2003;23:3001.
Dalley JW, et al. Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J Neurosci. 2001;21:4908.
Edwards FA. Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiological Reviews 1995; 75: 759–87.
Fadda F, Cocco S, Stancampiano R. A physiological method to selectively decrease brain serotonin release. Brain Res Brain Res Protoc. 2000;5:219.
Handra, Claudia, et al. "The connection between different neurotransmitters involved in cognitive processes." Farmacia 67.2 (2019): 193-201.
Hasselmo ME. Neuromodulation: acetylcholine and memory consolidation. Trends Cogn Sci. 1999;3:351.
Himmelheber AM, Sarter M, Bruno JP. Increases in cortical acetylcholine release during sustained attention performance in rats. Brain Res Cogn Brain Res. 2000;9:313.
Izquierdo, Ivan. "Role of NMDA receptors in memory." Trends in Pharmacological Sciences 12.4 (1991): 128-129.
J.L. McGaugh Memory—a century of consolidation Science, 287 (2000), pp. 248-251
J.L. McGaugh, I. Izquierdo The contribution of pharmacology to research on the mechanisms of memory formation Trends in Pharmacological Sciences, 21 (2000), pp. 208-210
Li S, Nai Q, Lipina TV, Roder JC, Liu F, α7nAchR/NMDAR coupling affects NMDAR function and object recognition. Mol Brain, 2013, 6: 1-10.
Lo DC. Neurotrophic factors and synaptic plasticity. Neuron 1995; 15: 979–81.
Lupușoru CE, Popa EG, Sandu RB, Buca BR, Mititelu-Tarțău L, Lupușoru RV, The influence of Bidens tripartita extracts on psychomotor abilities and cognitive functions in rats. Farmacia, 2017; 65(2): 284-288.
M.I. Miranda, F. Bermúdez-Rattoni Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories Proceedings of the National Academy of Sciences of the United States of America, 96 (1999), pp. 6478-6482
Marrosu F, et al. Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep–wake cycle in freely moving cats. Brain Res. 1995;671:329.
May-Simera H, Levin ED, NMDA systems in the amygdala and piriform cortex and nicotinic effects on memory function. Cogn Brain Res., 2003; 17:475-483
McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annual Review of Neuroscience 1999; 22: 295–318
McIntyre CK, Marriott LK, Gold PE. Cooperation between memory systems: acetylcholine release in the amygdala correlates positively with performance on a hippocampus-dependent task. Behav Neurosci. 2003;117:320.
Miranda MI, et al. Role of cholinergic system on the construction of memories: taste memory encoding. Neurobiol Learn Mem. 2003;80:211.
Miranda MI. Changes in Neurotransmitter Extracellular Levels during Memory Formation. In: Bermúdez-Rattoni F, editor. Neural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 7.
Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683
Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776
Muir JL, Everitt BJ, Robbins TW. The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex. 1996;6:470.
Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology, 2010; 42:151–160.
Orsetti M, Casamenti F, Pepeu G. Enhanced acetylcholine release in the hippocampus and cortex during acquisition of an operant behavior. Brain Res. 1996;724:89.
Power AE. Muscarinic cholinergic contribution to memory consolidation: with attention to involvement of the basolateral amygdala. Curr Med Chem. 2004;11:987.
Pych JC, et al. Acetylcholine release in hippocampus and striatum during testing on a rewarded spontaneous alternation task. Neurobiol Learn Mem. 2005;84:93.
Ragozzino ME, Unick KE, Gold PE. Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci USA. 1996;93:4693.
S. Kopf, M. Buchholzer, M. Hilgert, K. Loffelholz, J. Klein Glucose plus choline improves passive avoidance behavior and increases hippocampal acetylcholine release in mice Neuroscience, 103 (2001), pp. 365-371
Stancampiano R, et al. Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task. Neuroscience. 1999;89:1135.
Thoenen H. Neurotrophins and neuronal plasticity. Science 1995; 270: 593–8.