To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:359
Neuronal network function, Decreased leads to Impairment, Learning and memory
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Learning and memory is one of the outcomes of the functional expression of neurons and neural networks from mammalian to invertebrates. Damage or destruction of neurons by chemical compounds during development when they are in the process of synapses formation, integration and formation of neural networks, will derange the organization and function of these networks, thereby setting the stage for subsequent impairment of learning and memory. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment.
Impairments in learning and memory are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency (Wang et al., 2012; Oerbeck et al., 2003; Wheeler et al., 2011; Wheeler et al., 2015; Willoughby et al., 2014; Davenport and Dorcey, 1972; Tamasy et al., 1986; Akaike, 1991; Axelstad et al., 2008; Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016). A well-established functional readout of memory at the synaptic level is known as long-term potentiation (LTP) (i.e., a persistent strengthening of synapses based on recent patterns of activity). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments. In rodent models where synaptic function is impaired by TH deficiencies, deficits in hippocampus-mediated memory are also prevalent (Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016).
Evidence Collection Strategy
Evidence Supporting this KER
A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption, and leading to decreased cognition.
Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy and its discovery suggested that changes in synaptic strength could provide the substrate for learning and memory (reviewed in Lynch, 2004). 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 excitatory postsynaptic currents (EPSCs) to be developed quickly and to be persistent for few weeks at least without disturbing already potentiated contacts. Once again, a substantial body of evidence has demonstrated that tight connection between LTP and diverse instances of memory exist (reviewed in Lynch, 2004).
A review on Morris water maze (MWM) as a tool to investigate spatial learning and memory in laboratory rats also pointed out that the disconnection between neuronal networks rather than the brain damage of certain regions is responsible for the impairment of MWM performance. Functional integrated neural networks that involve the coordination action of different brain regions are consequently important for spatial learning and MWM performance (D'Hooge and De Deyn, 2001).
Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a number of studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI), as well as iodine deficient diets, to changes in serum TH levels, which result in alterations in both synaptic function and cognitive behaviors (Akaike et al., 1991; Vara et al., 2002; Gilbert and Sui, 2006; Axelstad et al., 2008; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016), described in the indirect KER "Decrease of TH synthesis leads to learning and memory deficits".
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 what modifications of 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.
The direct relationship of alterations in neural network function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function have been found in the absence of behavioral impairments. This may result from measuring only one component in the complex brain circuitry that underlies 'cognition', behavioral tests that are not sufficiently sensitive for the detection of subtle cognitive impairments, and behavioral plasticity whereby tasks are solved by the animal via different strategies developed as a consequence of developmental insult.
Finally, in order to provide empirical support for this KER, data on the effects of lead (Pb) exposure are reported. Several epidemiological studies where Pb2+ exposure levels have been studied in relation to neurobehavioural alterations in children have been reviewed in Koller et al. 2004. This review has concluded that in some occasions there is negative correlation between Pb2+ dose and cognitive deficits of the subjects due to high influence of social and parenting factors in cognitive ability like learning and memory (Koller et al. 2004), meaning that not always Pb2+ exposure is positively associated with learning and memory impairment in children.
Olczak et al., 2001. Postnatal exposure of rats to Thimerosal (4 injections with 12, 240, 1440 and 3000 microgHg/kg per injection). Effects were measured in adult, which exhibited alterations in dopaminergic system with decline in the density of striatal D2 receptors, with a higher sensitivity for males. No alterations in spatial learning and memory was observed, but impairments of motor activity, increased anxiety (open fiel measurment), which are other symptoms of autism spectrum disorder.
Franco et al., 2006. Lactational exposure of mice to methylmercury in drinking water (10 mg/L). Analysis at weaning revealed only impairment in motor performances.
Franco et al., 2007. Lactational exposure of mice with mercury chloride (0.5 and 1.5 mg/kg, i.p. injection once a day).. At weaning , animals exhibited an increased level of mercury in cerebellum associated with motor deficit.
Cardenas et al., 2017 showed that maternal red blood cell mercury of 3.8 ng/g was associated to increased DNA methylation of PON1 in umbilical cord blood only in male and observed deficit in cognitive performances, such as visual motor ability, vocabiary and verbal intellgence.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Synaptic transmission and plasticity are achieved via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats. Deficiencies in hippocampally based learning and memory following developmental hypothyroidism have been documented mainly in rodents and humans.
Akaike M, Kato, N., Ohno, H., Kobayashi, T. (1991). Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317-322.
Anderson DW, Pothakos K, Schneider JS. (2012). Sex and rearing condition modify the effects of perinatal lead exposure on learning and memory. Neurotoxicology 33: 985-995.
Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, U H. (2008). Developmental neurotoxicity of Propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol 232:1-13.
Baghurst PA, Tong S, Sawyer MG, Burns J, McMichael AJ. (1992). Environmental exposure to lead and children’s intelligence at the age of seven years. The Port Pirie Cohort Study. N Engl J Med. 327: 1279-1284.
Bellinger D, Sloman J, Leviton A, Rabinowitz M, Needleman HL, Waternaux C. (1991). Low-level lead exposure and children's cognitive function in the preschool years. Pediatrics. 87: 219-227.
Bellinger DC, Stiles KM, Needleman HL. (1992). Low-level lead exposure, intelligence and academic achievement: a long-term follow-up study. Pediatrics. 90: 855-861.
Bellinger DC. (2004). Lead. Pediatrics 113: 1016-1022.
Brockel BJ, Cory-Slechta DA. (1998). Lead, attention, and impulsive behavior: changes in a fixed-ratio waiting-for-reward paradigm. Pharmacol Biochem Behav. 60: 545-552.
Cagiano, R., et al. (1990). "Evidence that exposure to methyl mercury during gestation induces behavioral and neurochemical changes in offspring of rats." Neurotoxicol Teratol 12(1): 23-28.
Canfield RL, Henderson CR Jr, Cory-Slechta D, Cox C, Jusko TA, Lanphear BP. (2003). Intellectual impairment in children with blood lead concentrations below 10 μg per deciliter. N Engl J Med. 348: 1517-1526.
Cao X, Huang S, Ruan D. (2008). Enriched environment restores impaired hippocampal long-term potentiation and water maze performance induced by developmental lead exposure in rats. Dev Psychobiol. 50: 307-313.
Cardenas A, Rifas-Shiman SL, Agha G, Hivert MF, Litonjua AA, DeMeo DL, Lin X, Amarasiriwardena CJ, Oken E, Gillman MW, Baccarelli AA., Persistent DNA methylation changes associated with prenatal mercury exposure and cognitive performance during childhood., Sci Rep. 2017 Mar 21;7(1):288. doi: 10.1038/s41598-017-00384-5.
Cohn J, Cory-Slechta DA. (1993). Subsensitivity of lead-exposed rats to the accuracy-impairing and rate-altering effects of MK-801 on a multiple schedule of repeated learning and performance. Brain Res. 600: 208-218.
Cohn J, Cory-Slechta DA. (1994). Lead exposure potentiates the effects of N-methyl-D-asparate on repeated learning. Neurotoxicol Teratol. 16: 455-465.
Cory-Slechta DA. (1995). MK-801 subsensitivity following postweaning lead exposure. Neurotoxicology 16: 83-95.
de Souza Lisboa S F, Gonzalves G, Komatsu F, Salci Queiroz CA, Aparecido Almeida A, Gastaldello Moreira EN. (2005). Developmental lead exposure induces depressive-like behavior in female rats. Drug Chem Toxicol. 28: 67-77.
D'Hooge R, De Deyn PP. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 36: 60-90.
Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26:417-426.
Eddins, D., et al. (2008). "Mercury-induced cognitive impairment in metallothionein-1/2 null mice." Neurotoxicol Teratol 30(2): 88-95.
Finkelstein Y, Markowitz ME, Rosen JF. (1998). Low-level lead-induced neurotoxicity in children: an update on central nervous system effects. Brain Res Rev. 27: 168-176.
Franco, J. L., et al. (2006). "Cerebellar thiol status and motor deficit after lactational exposure to methylmercury." Environ Res 102(1): 22-28.
Franco, J. L., et al. (2007). "Lactational exposure to inorganic mercury: evidence of neurotoxic effects." Neurotoxicol Teratol 29(3): 360-367.
Gilbert ME, Kelly ME, Samsam TE, Goodman JH. (2005). Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning. Toxicol Sci. 86: 365-374.
Gilbert ME. (2011). Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci 124:432-445.
Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.
Gilbert ME, Sui L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.
Glover, C. N., et al. (2009). "Methylmercury speciation influences brain gene expression and behavior in gestationally-exposed mice pups." Toxicol Sci 110(2): 389-400.
Grunwald T, Beck H, Lehnertz K, Blümcke I, Pezer N, Kurthen M, Fernández G, Van Roost D, Heinze HJ, Kutas M, Elger CE. (1999). Evidence relating human verbal memory to hippocampal N-methyl-D-aspartate receptors. Proc Natl Acad Sci U S A. 96: 12085-12089.
Jaako-Movits K, Zharkovsky T, Romantchik O, Jurgenson M, Merisalu E, Heidmets LT, Zharkovsky A. (2005). Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain. Int J Dev Neurosci. 23: 627-635.
Jang YJ, Park HR, Kim TH, Yang WJ, Lee JJ, Choi SY, Oh SB, Lee E, Park JH, Kim HP, Kim HS, Lee J. (2012). High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations. Toxicology. Jun 14;296(1-3):73-82.
Jett DA, Kuhlmann AC, Farmer SJ, Guilarte TR. (1997). Age-dependent effects of developmental lead exposure on performance in the Morris water maze. Pharmacol Biochem Behav. 57: 271-279.
Jusko TA, Henderson CR, Lanphear BP, Cory-Slechta DA, Parsons PJ, Canfield RL. (2008). Blood lead concentrations < 10 microg/dL and child intelligence at 6 years of age. Environ Health Perspect 116:243-248.
Koller K, Brown T, Spurgeon A, Levy L. (2004). Recent developments in low-level lead exposure and intellectual impairment in children. Environ Health Perspect. 112: 987-994.
Kumar MV, Desiraju T. (1992). EEG spectral power reduction and learning disability in rats exposed to lead through postnatal developing age. Indian J Physiol Pharmacol. 36: 15-20.
Lanphear BP, Dietrich K, Auinger P, Cox C. (2000). Cognitive deficits associated with blood lead concentrations <10 microg/dL in US children and adolescents. Public Health Rep. 115: 521-529.
Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R. (2005). Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect. 113: 894-899.
Leviton A, Bellinger D, Allred EH, Rabinowitz M, Needleman H, Schoenbaum S. (1993). Pre- and postnatal low-level lead exposure and children's dysfunction in school. Environ Res 60:30-43.
Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H. (2010). The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid 20:909–915.
Lynch MA. (2004). Long-term potentiation and memory. Physiol Rev. 84: 87-136.
Mayford M, Siegelbaum SA, Kandel ER. (2012). Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751.
Montgomery, K. S., et al. (2008). "Chronic, low-dose prenatal exposure to methylmercury impairs motor and mnemonic function in adult C57/B6 mice." Behav Brain Res 191(1): 55-61.
Moreira EG, Vassilieff I, Vassilieff VS. (2001). Developmental lead exposure: behavioral alterations in the short and long term. Neurotoxicol Teratol. 23: 489-495.
Morris RG, 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.
Murphy KJ, Regan CM. (1999). Low level lead exposure in the early postnatal period results in persisting neuroplastic deficits associated with memory consolidation. J Neurochem. 72: 2099-2104.
Neal AP, Guilarte TR. (2010). Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function. Mol Neurobiol. 42: 151-160.
Needleman HL, Epstein S, Carnow B, Scanlon J, Parkinson D, Samuels S, Mazzochi A, David O. (1975). Letter: Blood-lead levels, behaviour and intelligence. Lancet 1: 751-752.
Needleman HL, Gatsonis CA. (1990). Low-level lead exposure and the IQ of children. A meta-analysis of modern studies. Jama 263: 673-678.
Needleman HL, Riess JA, Tobin MJ, Biesecker GE, Greenhouse JB. (1996). Bone Lead Levels and Delinquent Behavior. Jama 275: 363-369.
Olczak, M., et al. (2011). "Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats." Behav Brain Res 223(1): 107-118.
Onishchenko, N., et al. (2007). "Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice." Toxicol Sci 97(2): 428-437.
Orenstein, S. T., et al. (2014). "Prenatal organochlorine and methylmercury exposure and memory and learning in school-age children in communities near the New Bedford Harbor Superfund site, Massachusetts." Environ Health Perspect 122(11): 1253-1259.
Rice, D. C. (1992). "Effects of pre- plus postnatal exposure to methylmercury in the monkey on fixed interval and discrimination reversal performance." Neurotoxicology 13(2): 443-452.
Saar D, Barkai E. (2003). Long-term modifications in intrinsic neuronal properties and rule learning in rats. Eur J Neurosci. 17: 2727-2734.
Sahin, D., et al. (2016). "Effects of gestational and lactational exposure to low dose mercury chloride (HgCl2) on behaviour, learning and hearing thresholds in WAG/Rij rats." EXCLI J 15: 391-402.
Salinas JA, Huff NC. (2002). Lead and conditioned fear to contextual and discrete cues. Neurotoxicol Teratol. 24: 541-550.
Sokolowski, K., et al. (2013). "Neural stem cell apoptosis after low-methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits." Dev Neurobiol 73(12): 936-949.
Surkan PJ, Zhang A, Trachtenberg F, Daniel DB, McKinlay S, Bellinger DC. (2007). Neuropsychological function in children with blood lead levels <10 microg/dL. Neurotoxicology. 28: 1170-1177.
Sui L, Anderson WL, Gilbert ME. (2005). Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647-656.
Sui L, Gilbert ME. (2003). Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195-4203.
Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. (2008). Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology 149:3521-3530.
Toscano CD, Guilarte TR. (2005). Lead neurotoxicity: From exposure to molecular effects. Brain Res Rev. 49: 529-554.
Vara H, Martinez B, Santos A, Colino A. (2002). Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19-28.
Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848.
Wheeler SM, McAndrews MP, Sheard ED, Rovet J. (2012). Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism. J Int Neuropsychol Soc 18:49-56.
Wheeler SM, McLelland VC, Sheard E, McAndrews MP, Rovet JF. (2015). Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism. Front Endocrinol (Lausanne) 6:163.
Willoughby KA, McAndrews MP, Rovet J. (2013). Effects of early thyroid hormone deficiency on children's autobiographical memory performance. J Int Neuropsychol Soc 19:419-429.
Willoughby KA, McAndrews MP, Rovet JF. (2014). Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid 24:576-584.
Wu Y, Beland FA1, Fang JL. (2016). Effect of triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis. Toxicol In Vitro. Apr;32:310-9.
Xiao Y, Fu H, Han X, Hu X, Gu H, Chen Y, Wei Q, Hu Q. (2014). Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats. PLoS One. 23;9(12):e115556.
Xu J, Yan HC, Yang B, Tong LS, Zou YX, Tian Y. (2009). Effects of lead exposure on hippocampal metabotropic glutamate receptor subtype 3 and 7 in developmental rats. J Negat Results Biomed. 8: 5.
Yorifuji, T., et al. (2011). "Long-term exposure to methylmercury and psychiatric symptoms in residents of Minamata, Japan." Environ Int 37(5): 907-913.
Zanoli, P., et al. (1994). "Methyl mercury during late gestation affects temporarily the development of cortical muscarinic receptors in rat offspring." Pharmacol Toxicol 75(5): 261-264.
Zanoli, P., et al. (2001). "Prenatal exposure to methyl mercury in rats: focus on changes in kynurenine pathway." Brain Res Bull 55(2): 235-238.