An Interaction Between Thyroid Hormone and Nerve Growth Factor Promotes the Development of Hippocampus, Olfactory Bulbs and Cerebellum: a Comparative Biochemical Study of Normal and Hypothyroid Rats

The effects of treatment with L-thyroxine (T-4; 20 ng/g body weight, given subcutaneously on days 1, 3, 5, 7 and 9), 2.5 S nerve growth factor (NGF; 2 ng/mg brain wet weight, given intracerebroventricularly on days 1, 3, 5, 7 and 9), monoclonal anti-NGF (2 ng/mg wet weight, given intracerebroventricularly on days 1, 3, 5, 7 and 9), and monoclonal anti-NGF receptor (192 IgG; 2 ng/mg wet weight, injected daily from day 1 to day 9) antibodies, separately or together, were studied on the biochemical development of hippocampal formation, olfactory bulbs and cerebellum in 10-day-old and 15-day-old normal and hypothyroid rats. The results provide the following information: (1) CNS structures other than the basal forebrain are sensitive to NGF during early development. (2) Both normal and hypothyroid rats are more sensitive to NGF deprivation than NGF supplementation. (3) The effects of anti-NGF antibodies in normal rats are similar to those induced by anti-NGFr antibodies. (4) NGF alone had little or no effect, but interacts with T-4 in promoting cell maturation, especially in hypothyroid rats. (5) Hypothyroid rats are more sensitive to T-4 and to T-4 plus NGF than are normal ones. (6) The synergistic action of both trophic factors, but not that of T-4, tend to disappear at long term in hypothyroid rats. (7) The differential sensitivity of the brain areas to T-4, NGF, or both trophic factors correlates with their cell acquisition rate, especially in hypothyroid rats. (8) T-4 and NGF together act more markedly (but not exclusively) on the cholinergic structures in both normal and hypothyroid rats. (9) RNA appears to be very sensitive to NGF, especially in hypothyroid rats. In close correlation with preliminary morphological observations, the results clearly demonstrate that an interaction between T-4 and NGF regulates the ontogeny of a number of neuronal structures in CNS independently of their neurotransmitter phenotype, but with a regional specificity. The possibilities of accounting for this interaction, in particular the major role of thyroxine, are discussed.