Recent studies have caused concern regarding the long term neurological outcome of preterm infants with hypothyroxinemia (New Engl J 334:821-827, 1996) & full term infants with thyroxine treated congenital hypothyroidism(hypoT) (Ped Res 39:561-566, 1996). To understand the metabolic mechanisms underlying hypoT induced adverse effects upon neurological function, we previously examined its effect upon brain glucose transporters and noted a 50% decline (Ped Res 39:91A, 1996). In this study we investigated the expression and role of the hexokinase I (hxl) enzyme which mediates brain glucose phosphorylation, a rate limiting process critical for brain cellular growth, maturation and oxidative metabolism. Employing the hyt/hyt mouse which expresses a native mutation (Pro556→Leu) of the TSH receptorβ-subunit and presents phenotypically with congenital primary hypoT (Endo 136:1346-1353, 1995) & the Balb-C (+/+) mouse as the control, we examined the brain hxl mRNA (Northern blot), protein concentrations (Western blot), enzymatic activity (NADP→NAPH spectrophotometric assay) & function(brain 3H-2deoxy[2-D] glucose uptake [GU]) at 1d, 14d, & 35d (n=6 per group) postnatal ages. In the hyt/hyt mice an increase in hxl mRNA was noted at 14d (40%; p < 0.05) & 35d (2-fold; p < 0.05), while a 50% increase in hxl protein levels (p < 0.05) was observed at 35d. In contrast, Hxl enzyme activity & H-2-DGU/mg declined only in the 14d hyt/hyt vs. Balb-C mice. We conclude that 1] hypoT post-translationally decreases brain hxl enzyme activity and 2-DGU at 14d postnatal age, similar to our previous observation of a decline in brain glucose transporter protein levels, 2] in response to the hypoT induced decline in brain GU & hxl activity, hxl mRNA & protein concentrations demonstrated a compensatory increase. We speculate that hypoT adversely affects brain GU by reducing brain glucose phosphorylation only at 14d, a period when a physiological thyroid hormone surge, and maximal brain growth and cellular maturation occurs, thereby explaining the development of neurological dysfunction.

[Supported by NIH HD-33997 & HL-52839]