Infrapyramidal Mossy Fibers in the Hippocampus of the Hyperthyroid Rat

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Abstract
Hyperthyroidism, initiated at birth, produces an infrapyramidal (IP) bundle of mossy fibers in stratum oriens of field CA3a-b of Ammon''s horn. The distribution of these axons, their mode of passage to the infrapyramidal region, and their synaptic relationship to the basal pyramidal cell dendrites were studied using the Timm-Haug silver sulfide method, rapid Golgi, and electron microscopy. Terminals of the hyperthyroid IP mossy fibers were consistently found to synapse with ''excrescences'' on the basal pyramidal cell dendrites in field CA3a-b at all levels of the hippocampus. The excrescences, normally characteristic of synapses between the suprapyramidal mossy fibers and apical pyramidal cell dendrites are uncommon on the basal pyramidal cell dendrites of CA3a-b in untreated animals except at septodorsal levels where a few are found in association with a small number of IP mossy fibers. The apparently exclusive association of excrescences with mossy fiber boutons even when they are in an ectopic position suggests that the mossy fibers may have the ability to induce formation of these postsynaptic specializations oh their pyramidal cell targets during development. Topographic differences with respect to the magnitude of the hyperthyroid effect at different anatomical levels were also observed. For example, although IP mossy fibers were numerous in CA3a-b at the midseptotemporal level, this effect was even more pronounced at septodorsal levels. These differences may reflect the interaction of the hyperthyroid state with certain developmental relationships such as the temporoseptal gradient for granule cell generation and the septotemporal gradient for development of cholinergic afferents to stratum oriens. Since thyroid hormone requires immature cells to exert its differentiation related effects, the more immature IP mossy fibers at septodorsal levels might react more strongly to the growth stimulating effect of hyperthyroidism and thus be able to successfully compete for postsynaptic sites on the basal pyramidal cell dendrites. In untreated animals, the presence of a small number of IP mossy fibers in CA3a-b at septodorsal levels might reflect these same spatio-temporal relationships during phases of hippocampal development normally modulated by thyroid hormone. Formation of the IP mossy fiber bundle in hyperthyroidism is dose dependent, raising the possibility that it results from a direct effect of excess thyroxine on axonal growth. Furthermore, it is long-lasting indicating that the mossy-fiber pyramidal cell circuitry is permanently altered. Finally, the ''critical period'' for its production occurs within the first 3 weeks after birth which coincides with the main period of granule cell generation and mossy fiber development in the rat. This experimentally produced aberration in the development of intrinsic connections emphasizes the importance of temporal factors and their hormonal modulation in postnatal hippocampal ontogeny. Future studies of circuitry construction in this discrete hodologic system may benefit from the use of hyperthyroidism as an analytical tool.