Thyroid Hormone Influence on the Susceptibility of Mice to Audiogenic Seizures

Seyfried, Thomas N.; Glaser, Gilbert H.; Yu, Robert K.

doi:10.1126/science.451624

Cited by 60 publications

(21 citation statements)

References 20 publications

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“…Total T4 levels increased between P5 and P16 and declined slightly thereafter, until at P21, after weaning, concentrations began to increase to adult levels. This profile resembled that reported for estimated free T4 levels in mice (34). The total T3 profile paralleled that of T4.…”

Section: Resultssupporting

confidence: 70%

Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing

Campos-Barros

Amma

Faris

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

134

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Thyroid hormone signaling during a postnatal period in the mouse is essential for cochlear development and the subsequent onset of hearing. To study the control of this temporal dependency, we investigated the role of iodothyronine deiodinases, which in target tissues convert the prohormone thyroxine into triiodothyronine (T3), the active ligand for the thyroid hormone receptor (TR). Type 2 5 -deiodinase (D2) activity rose dramatically in the mouse cochlea to peak around postnatal day 7 (P7), after which activity declined by P10. This activity peak a few days before the onset of hearing suggests a role for D2 in amplifying local T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA was isolated and demonstrated near identity to rat D2. In situ hybridization localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear outer capsule and the septal divisions between the turns of the cochlea. Surprisingly, D2 expression in these regions that give rise to the bony labyrinth was complementary to TR expression in the sensory epithelium. Thus, the connective tissue may control deiodination of thyroxine and release of T3 to confer a paracrine-like control of TR activation. These results suggest that temporal and spatial control of ligand availability conferred by D2 provides an unexpectedly important level of regulation of the TR pathways required for cochlear maturation.development ͉ thyroid hormone receptor ͉ deiodinase ͉ cochlea O ne of the most sensitive functions controlled by thyroid hormone (TH) is the development of hearing, as is evident from the deafness associated with human congenital hypothyroidism. Experimental hypothyroidism in rodents has revealed that the cochlea is a major site of TH action and has shown that cochlear maturation and the onset of auditory function around postnatal day 14 (P14) require TH during a critical period between the late embryonic stage and the second postnatal week (1-3). This developmental window is strictly delineated, because TH can rescue cochlear morphogenesis and auditory function in hypothyroid mice or rats if provided during early postnatal stages but not after P10-P12. Little is known of the mechanisms that control this temporal regulation.TH receptors (TR) play a critical role in the auditory system (4). TR␣1 and TR␤, encoded by two related genes, are nuclear receptors that act as ligand-dependent transcription factors (5, 6). TR␣1 and TR␤ are expressed in the cochlea with TR␤ mRNA being prominent both in the embryonic otic vesicle and in the postnatal sensory epithelium and spiral ganglion (7-9). TR␤-deficient mice and humans are severely deaf, as assessed by defective auditory-evoked brainstem responses (10, 11), whereas TR␣1-deficient mice have a normal auditory-evoked brainstem response (12). Mild hearing defects occur in Ϸ20% of cases of the human syndrome of resistance to thyroid hormone, which is associated with TR␤ point mutations (13).The control of ligand availability in target tissues constitutes another level of ...

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Section: Resultssupporting

confidence: 70%

Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing

Campos-Barros

Amma

Faris

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

134

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“…Conversely, significantly higher serum T4 levels were shown in audiogenic seizure-susceptible DBA/2J mice than in seizure-resistant C57BL/6J mice, transiently during early postnatal life (Seyfried et al 1979). Anyway, several species differences exist between GEPRs and DBA/2J mice (Chapman et al 1984;Consroe et al 1979;Dailey et al 1989;Faingold 1988;Reiget et al t986), particularly the phase in life with a most intense susceptibility to audiogenic seizures.…”

Section: Discussionmentioning

confidence: 94%

Evaluation of local cerebral glucose utilization and the permeability of the blood-brain barrier in the genetically epilepsy-prone rat

et al. 1992

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The genetically epileptic-prone rat (GEPR) is a valuable model for the study of gene-linked abnormalities involved in epilepsy. In comparison with normal Sprague-Dawley controls, we found, in GEPRs, a marked depression in local cerebral glucose utilization, widespread throughout the brain. This depression was accompanied by a significant increase of blood-brain barrier permeability and a reduction in regional blood volume. Finally GEPRs showed lower plasma levels of total triiodothyronine than normal controls. One can speculate that alterations in cerebral metabolism and microvascular regulation and thyroid hormone imbalance may be gene-linked factors involved in seizure susceptibility.

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“…Study of ganglioside changes associated with temporal lobe epilepsy in the human hippocampus revealed a loss of GD1a (disialo analog of GM1) that was attributed to neuronal destruction and an increase in GD3 (a nongangliotetraose ganglioside) that was attributed to localized accumulation of reactive glia . It is well recognized that seizure activity is a complex process (Seyfried et al, 1979;Engel et al, 1997;Buckmaster et al, 2002) and that ganglioside changes are not the sole cause or result of such pathology.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Susceptibility to Kainate-Induced Seizures, Neuronal Apoptosis, and Death in Mice Lacking Gangliotetraose Gangliosides: Protection with LIGA 20, a Membrane-Permeant Analog of GM1

Wang

et al. 2005

J. Neurosci.

103

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Knock-out (KO) mice lacking gangliotetraose gangliosides attributable to disruption of the gene for GM2/GD2 synthase [GalNAcT (UDP-N-acetylgalactosamine:GM3/GD3 ␤-1,4-N-acetylgalactosaminyltransferase; EC 2.4.1.92)] are revealing key neural functions for the complex gangliosides of brain. This study has found such animals to be highly susceptible to kainic acid (KA)-induced seizures in terms of both seizure severity and duration. Intraperitoneal injection of 25 mg/kg KA produced status epilepticus for ϳ200 min in normal mice or heterozygotes and more than four times longer in the KO mice. The latter group suffered ϳ30% mortality, which increased to ϳ75% at dosage of 30 mg/kg KA, compared with 10 -14% for the other two genotypes at the latter dosage. Nissl staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay revealed substantial deterioration of pyramidal neurons attributable to apoptosis in the KO hippocampus, especially the CA3 region. Seizure activity in the KO mouse was only moderately diminished by intraperitoneal injection of GM1 ganglioside, whereas LIGA 20, a semisynthetic analog of GM1, substantially reduced both seizure severity and cell damage. The potency of LIGA 20 was correlated with its enhanced membrane permeability (compared with GM1), as seen in the increased uptake of /Ca2ϩ exchanger located at the inner membrane of the nuclear envelope in KO mice, an exchanger dependent on tight association with GM1 or its analog for optimal activity. These results point to a neuroprotective role for GM1 and its associated exchanger in the nucleus, based on regulation of Ca 2ϩ flux between nucleoplasm and nuclear envelope.

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Thyroid Hormone Influence on the Susceptibility of Mice to Audiogenic Seizures

Cited by 60 publications

References 20 publications

Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing

Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing

Evaluation of local cerebral glucose utilization and the permeability of the blood-brain barrier in the genetically epilepsy-prone rat

Enhanced Susceptibility to Kainate-Induced Seizures, Neuronal Apoptosis, and Death in Mice Lacking Gangliotetraose Gangliosides: Protection with LIGA 20, a Membrane-Permeant Analog of GM1

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