Deficiency of Thyroid Hormone Reduces Voltage-Gated Na(+) Currents as Well as Expression of Na(+)/K(+)-ATPase in the Mouse Hippocampus

Mice lacking functional thyroid follicular cells, Pax8(−/−) mice, die early postnatally, making them suitable models for extreme hypothyroidism. We have previously obtained evidence in postnatal rat neurons, that a down-regulation of Na(+)-current density could explain the reduced excitability of the nervous system in hypothyroidism. If such a mechanism underlies the development of coma and death in severe hypothyroidism, Pax8(−/−) mice should show deficits in the expression of Na(+) currents and potentially also in the expression of Na(+)/K(+)-ATPases, which are necessary to maintain low intracellular Na(+) levels. We thus compared Na(+) current densities in postnatal mice using the patch-clamp technique in the whole-cell configuration as well as the expression of three alpha and two beta-subunits of the Na(+)/K(+)-ATPase in wild type versus Pax8(−/−) mice. Whereas the Na(+) current density in hippocampal neurons from wild type mice was upregulated within the first postnatal week, the Na(+) current density remained at a very low level in hippocampal neurons from Pax8(−/−) mice. Pax8(−/−) mice also showed significantly decreased protein expression levels of the catalytic α1 and α3 subunits of the Na(+)/K(+)-ATPase as well as decreased levels of the β2 isoform, with no changes in the α2 and β1 subunits.