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Functional Activation of Cerebral Metabolism in Mice with Mutated Thyroid Hormone Nuclear Receptors

Laboratory of Cerebral Metabolism, National Institute of Mental Health (T.E., M.C., L.S., J.N.); Positron Emission Department, Clinical Center (K.S.); and Laboratory of Molecular Biology, National Cancer Institute (H.S., S.-Y.C.), National Institutes of Health, Bethesda, Maryland 20892

Address requests for reprints to: Dr. Louis Sokoloff, Laboratory of Cerebral Metabolism, National Institute of Mental Health, Building 36, Room 1A-07, 36 Convent Drive, MSC 4030, Bethesda, Maryland 20892. E-mail: louis{at}shiloh.nimh.nih.gov.

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 1 (TR1), but not TRß. 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 TR1^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 TR1^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 TR1^PV/+ mutants that were as great as those in wild-type mice. These results indicate that in the TR1^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.

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