Functional activation of cerebral metabolism in mice with mutated thyroid hormone nuclear receptors.
Neonatal hypothyroidism impairs structural maturation in the brain and results in diminished electrical activities and energy metabolism. We recently found that glucose utilization (CMR(glc)) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor alpha1 (TR alpha 1), but not TR beta. Previous studies had shown that CMR(glc) increases linearly with spike frequency in the afferent pathways to synapse-rich regions in neuropil, but not in neuronal cell bodies. To determine whether the decreased CMR(glc) in mutant TR alpha 1(PV/+) mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMR(glc) bilaterally in four stations of the whisker-to-barrel cortex pathway. Baseline CMR(glc) (unstimulated side) was markedly lower in all four stations in the TR alpha 1(PV/+) mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na(+),K(+)-adenosine triphosphatase expression and neuronal differentiation. Despite the lower baseline CMR(glc), however, vibrissal stimulation evoked percent increases in CMR(glc) in the TR alpha 1(PV/+) mutants that were as great as those in wild-type mice. These results indicate that in the TR alpha 1(PV/+) mutants there it is a reduction in synaptic density that is responsible for the decrease in CMR(glc), but functionality of existing synapses is retained.
Esaki
Takanori
T
Laboratory of Cerebral Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, MAryland 20892, USA.
Suzuki
Hideyo
H
Cook
Michelle
M
Shimoji
Kazuaki
K
Cheng
Sheue-Yann
SY
Sokoloff
Louis
L
Nunez
Jacques
J
D000818:Animals; D000906:Antibodies; D001345:Autoradiography; D002250:Carbon Radioisotopes; D002467:Cell Nucleus / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000276:immunology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013003:Somatosensory Cortex / Q000166:cytology / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta; D014278:Trigeminal Nuclei / Q000166:cytology / Q000378:metabolism; D014279:Trigeminal Nucleus, Spinal / Q000166:cytology / Q000378:metabolism; D020651:Ventral Thalamic Nuclei / Q000166:cytology / Q000378:metabolism; D014738:Vibrissae / Q000502:physiology
D000906:Antibodies; D002250:Carbon Radioisotopes; D007527:Isoenzymes; D008869:Microtubule-Associated Proteins; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D003847:Deoxyglucose; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose