Thyroid Hormone Homeostasis and Action in the Type 2 Deiodinase-Deficient Rodent Brain during Development

Abstract

Considerable indirect evidence suggests that the type 2 deiodinase (D2) generates T3 from T4 for local use in specific tissues such as pituitary, brown fat, and brain, and studies with a D2-deficent mouse, the D2 knockout (D2KO) mouse, have shown this to be the case in pituitary and brown fat. The present study employs the D2KO mouse to determine the role of D2 in the developing brain. As expected, the T3 content in the neonatal D2KO brain was markedly reduced to a level comparable with that seen in the hypothyroid neonatal wild-type mouse. However, the mRNA levels of several T3-responsive genes were either unaffected or much less affected in the brain of the D2KO mouse than in that of the hypothyroid mouse, and compared with the hypothyroid mouse, the D2KO mouse exhibited a very mild neurological phenotype. The current view of thyroid hormone homeostasis in the brain dictates that the T3 present in neurons is generated mostly, if not exclusively, from T4 by the D2 in glial cells. This view is inadequate to explain the findings presented herein, and it is suggested that important compensatory mechanisms must be in play in the brain to minimize functional abnormalities in the absence of the D2.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Parallel studies using mice deficient in one or more of the deiodinases will shed light on the relative importance of the different metabolic pathways. Several extraction procedures have been published and care must be taken to determine and correct for extraction efficiency (83,187).…”

“…A disruption in the D2 pathway has been shown to decrease T 3 production locally and disrupt thyroid hormone signaling in D2-expressing cells (92,173,(232)(233)(234). This is illustrated by the approximately 50% reduction in T 3 content in the D2 KO brain (187). D2 inhibitors can be used but with caution due to off-target effects.…”

“…Open-field testing protocols have been used to quantitate locomotor activity for distance travelled and speed over a defined period (187,483,511) in order to investigate both behavioral and stamina aspects of neuromuscular function in response to alterations in thyroid status. Motor and muscle function can be investigated by standardized tests of strength, including grip strength determined using an automated grip strength meter, an electronic pull strain gauge, or a hanging wire test (478).…”

“…Motor and muscle function can be investigated by standardized tests of strength, including grip strength determined using an automated grip strength meter, an electronic pull strain gauge, or a hanging wire test (478). Accelerating rotarod testing of balance and motor coordination is performed by determining the time an individual mouse is able to stay on the rod during its rotation following a defined training period prior to testing (187,483). Beam walk testing using a series of elevated beams of differing widths may be used to determine balance by measurement of foot slippage and time to cross the length of the beam (478).…”

“…Beam walk testing using a series of elevated beams of differing widths may be used to determine balance by measurement of foot slippage and time to cross the length of the beam (478). Alternatively, vertical pole tests are used to investigate agility and balance by determining the time taken for a mouse to invert and run to the base of a pole when placed near the top (187). Footprint analysis of gait can be assessed in mice trained to walk along a filter paper with their feet painted with different color nontoxic paints applied to forelimbs and hindlimbs.…”