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Synaptogenesis, Decreased leads to Neuronal network function, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||adjacent||Low||Anna Price (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||adjacent||Low||Low||Anna Price (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
The ability of a neuron to communicate is based on neural network formation that relies on functional synapse establishment (Colón-Ramos, 2009). The main roles of synapses are the regulation of intercellular communication in the nervous system, and the information flow within neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed. Therefore, the decreased synapse formation during the process of synaptogenesis is critical and leads to decrease of neural network formation and function in the adult brain.
Synaptic transmission and plasticity require the integrity of the anatomical substrate. The connectivity of axons emanating from one set of cells to post-synaptic side of synapse on the dendrites of the receiving cells must be intact for effective communication between neurons. Changes in the placement of cells within the network due to delays in neuronal migration, the absence of a full formation of dendritic arbors and spine upon which synaptic contacts are made, and the lagging of transmission of electrical impulses due to insufficient myelination will individually and cumulatively impair synaptic function. Since synaptogenesis follows the early neurodevelopmental processes such as neuronal and glial cells proliferation, migration, alterations in dendritic arborisation etc., therefore, it encompasses, possible changes in these early stages of brain development that could also be triggered under hypothyroidism, leading to defective synaptogenesis and resulting in abnormal function of neuronal network function. These anatomical alterations are responsible for many structural anomalies reported in various regions of the brain following severe developmental hypothyroidism. Although the primary evidence of synaptic transmission impairments in hypothyroid models have come from studying the hippocampus, it is assumed that the role thyroid hormones play in these processes is likely similar across different brain regions. Altered hippocampal structure induced by decreased TH levels impacts neurogenesis in the developing hippocampus or cortex, contributing to deficits in synaptic function.
Evidence Supporting this KER
The weight of evidence supporting the relationship between decreased synaptogenesis induced by TH insufficiency and altered neuronal network and synaptic function is moderate. Functional change as exemplified by alterations in synaptic transmission may be more easily detected than structural abnormalities. The exact alignment between the neuroanatomical effects (such as decreased synaptogenesis and alteration of GABAergic interneurons) that have been associated with developmental hypothyroidism (e.g., elicited by exposing rat dams to TPO inhibitors) and the neurophysiological impairments has not been entirely elucidated.
Neuronal network formation and function are established via the process of synaptogenesis. The developmental period of synaptogenesis is critical for the formation of the basic circuitry of the nervous system, although neurons are able to form new synapses throughout life (Rodier, 1995). The brain electrical activity dependence on synapse formation is critical for proper neuronal communication.
Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008). Indeed, knockdown of PSD-95 arrests the functional and morphological development of glutamatergic synapses (Ehrlich et al., 2007).
The biological plausibility of the known effects of TH insufficiency on brain structure having an impact on synaptic function and plasticity in brain is strong. Reductions in myelination of axons, cell number, dendritic arborization, and synaptogenesis have been described in models of severe hormone deprivation, as comprehensively summarized by Thompson and Potter, 2000. Because synaptic transmission relies on the integrity of synaptic contacts and the electrical and chemical transmission between pre- and post-synaptic neurons, it is well accepted that interference with process of synapse formation (morphological unit of neuronal network) will very much impact the neural network function.
Uncertainties and Inconsistencies
The exact mechanism by which a change in cell number, reduced dendritric arborization and synaptogenesis may lead to decreased neuronal network function has not been fully elucidated. Dose-dependent reductions in synaptic function in hippocampus have been demonstrated in models of moderate degrees of TH reduction, but studies of the anatomical integrity of the specific cell populations examined electrophysiologically have largely been evaluated in models of severe hypothyroidism and often in brain regions distinct from the hippocampus.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The main proof of evidence comes from in vivo studies in rodents. However, Colón-Ramos (2009) has recently reviewed the early developmental events that take place during the process of synaptogenesis in invertebrates, pointing out the importance of this process in neural network formation and function. The experimental findings reviewed in this paper derive from knowledge acquired in the field of neuroscience using C. elegans and Drosophila; at the same time, emerging findings derived from vertebrates are also discussed (Colón-Ramos, 2009).
Cline H, Haas K. (2008). The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis. J Physiol 586: 1509-1517.
Colón-Ramos DA. (2009). Synapse formation in developing neural circuits. Curr Top Dev Biol. 87: 53-79.
Di Liegro I, Savettieri G, Coppolino M, Scaturro M, Monte M, Nastasi T, Salemi G, Castiglia D, Cesterlli A (1995). Expression of synapsin I gene in primary cultures of differentiating rat cortical neurons. Neurochem. Res., 20, pp. 239–243
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.
Ehrlich I, Klein M, Rumpel S, Malinow R. (2007). PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A. 104: 4176-4181.
Gilbert ME. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev Brain Res 148:11-18.
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, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. (2013). An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.
Gilbert ME, Paczkowski C. (2003). Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res 145:19-29.
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.
Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH. (2007). Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92-102.
Herdegen T, Skene P, Bahr M (1997). The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci, 20, pp. 227–231
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.
Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM. (1991). Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171-186.
Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM. (1992). Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518.
McCarren M, Eccles CU. (1983). Neonatal lead exposure in rats: II. Effects on the hippocampal afterdischarge. Neurobehav Toxicol Teratol. 5: 533-540.
Otto D, Reiter L. (1984). Developmental changes in slow cortical potentials of young children with elevated body lead burden. Neurophysiological considerations. Ann N Y Acad Sci. 425: 377-383.
Rami A, Patel AJ, Rabie A. (1986a). Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217-1226.
Rami A, Rabie A, Patel AJ. (1986b). Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207-1216.
Rami A, Rabie A. (1990). Delayed synaptogenesis in the dentate gyrus of the thyroid-deficient developing rat. Dev Neurosci 12:398-405.
Rodier PM. (1995). Developing brain as a target of toxicity. Environ. Health Perspect. 103: 73-76.
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.
Thompson CC, Potter GB. (2000). Thyroid hormone action in neural development. Cereb Cortex. Oct;10(10):939-45.
Vara H, Martinez B, Santos A, Colino A. (2002). Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19-28.