Thyroid hormones as neurotransmitters

Abstract

During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.