Event:756

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Event Title

Hippocampal gene expression, Altered

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Moderate
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Moderate
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Moderate
Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity KE

Taxonomic Applicability

Name Scientific Name Evidence Links
mouse Mus sp. Strong NCBI
rats Rattus sp. Strong NCBI
Homo sapiens Homo sapiens Strong NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

Gene expression profiles have been published for the developing human and rodent hippocampus (Zhang et al., 2002; Mody et al., 2001). In both humans and rodents, the hippocampus undergoes typical stages of neurodevelopment found in most brain regions, including: cell proliferation, migration, differentiation, synapse formation, and the maturation of synaptic function. In the rodent, peak windows during pre and postnatal period have been identified during which major cellular and physiological events occur (see Figure 1). Each window expresses distinct patterns of gene transcription and clusters of genes increase their expression corresponding to the progression of events of hippocampal ontogeny (see Mody et al., 2001). Tables of gene clusters associated with these phases of can be found in Supplementary Tables of Mody et al. (2001).

INSERT FIGURE HERE

During the very early prenatal period, genes corresponding to general cellular function are prominent (Mody et al., 2001). These are followed in time by genes regulating neuronal differentiation and migration in the mid to late gestational period. From late gestation (gestational day 15) until birth almost all of the cells in the CA fields switch from a highly active proliferation state to a postmitotic state, and undergo differentiation and migration. As such, expression of proliferative genes involved in cell cycle progression are highly expressed at gestational day 16, then subsequently are silent immediately after birth when gene directing neuronal growth switch on. The pyramidal neurons of the CA fields in the hippocampus proper develop in advance of the granule cells that comprise the principal cells of the dentate gyrus and as such the genes controlling the distinct phases are expressed a different times in these two subregions (Altman and Bayer, 1990a; b). In both subregions, many phenotypic changes within the hippocampal neuron occur in the period immediately after birth (postnatal day 1 to 7). Almost all neurons show extensive growth and differentiation during the first postnatal week. These cellular changes are marked by rapid cytoskeletal changes, production of cell adhesion molecules, and extracellular matrix formation. The gene families involved in these processes include actins, tubulins, and chaperon proteins essential for promoting correct protein folding of cytoskeletal components. Cell adhesion and extracellular matrix proteins are also upregulated during this period as these genes are critical for differentiation and synaptogenesis.

During late postnatal hippocampal development (postnatal day 16-30), hippocampal circuits become more active and exhibit increased plasticity. Many genes upregulated during this phase of development are involved in synaptic function and include genes regulating vesicle associated proteins and calcium-mediated transmitter release, neurotrophins and neurotransmitter receptors. Efficient energy utilization is essential during this period of increased synaptic activity, events mirrored by an upregulation of enzymes involved in glucose and oxidative metabolism.

How it is Measured or Detected

Measurement of genomic profiles in developing brain use methods that are well established and accepted in the published literature. Microarray studies with expression profile analyses have been conducted in cortex and hippocampus of humans (Zhang et al., 2002), non-human primates, and rodent brain various ages (Mody et al., 2001; Royland et al., 2008; Dong et al., 2015). More commonly, quantitative rtPCR or in situ hybridization have been used to probe individual gene transcripts (Dowling et al., 2000, Morte et al., 2010) or their protein products (Alvarez-Dolado et al., 1994; Gilbert et al., 2007). Recently RNA-Seq technology was applied to T3-treated primary mouse cortical cells and gene targets enriched in astrocytes and neurons to identify TH-responsive genes (Gil-Ibanez et al, 2015).

Evidence Supporting Taxonomic Applicability

Gene expression in the developing brain in general is analogous across most mammalian species. Most of the empirical data on gene expression in hippocampus is from rat, mouse and human studies.

References

Altman J, Bayer SA. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol. 1990a Nov 15;301(3):365-81.

Altman J, Bayer SA. Prolonged sojourn of developing pyramidal cells in the intermediate zone of the hippocampus and their settling in the stratum pyramidale. J Comp Neurol. 1990b Nov 15;301(3):343-64.

Alvarez-Dolado M, Ruiz M, Del Rio JA, Alcantara S, Burgaya F, Sheldon M, Nakajima K, Bernal J, Howell BW, Curran T, Soriano E, Munoz A (1999) Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19:6979-6993.

Dong H, You SH, Williams A, Wade MG, Yauk CL, Thomas Zoeller R (2015) Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study. Cereb Cortex 25:1735-1745.

Dowling AL, Zoeller RT. 2000. Thyroid hormone of maternal origin regulates the expression of RC3/neurogranin mRNA in the fetal rat brain. Brain research Molecular brain research. Oct 20;82:126-132.

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.

Gil-Ibanez P, Garcia-Garcia F, Dopazo J, Bernal J, Morte B. 2015. Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types. Cerebral cortex. Nov 2.

Mody M, Cao Y, Cui Z, Tay KY, Shyong A, Shimizu E, Pham K, Schultz P, Welsh D, Tsien JZ. Genome-wide gene expression profiles of the developing mouse hippocampus. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8862-7.

Morte B, Ceballos A, Diez D, Grijota-Martinez C, Dumitrescu AM, Di Cosmo C, Galton VA, Refetoff S, Bernal J. 2010. Thyroid hormone-regulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice. Endocrinology. May;151:2381-2387.

Royland JE, Parker JS, Gilbert ME. A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol. 2008 Dec;20(12):1319-38.

Zhang Y, Mei P, Lou R, Zhang MQ, Wu G, Qiang B, Zhang Z, Shen Y. Gene expression profiling in developing human hippocampus. J Neurosci Res. 2002 Oct 15;70(2):200-8.