Ontogeny of human brain dopamine receptors. I. Differential expression of [3H]-SCH23390 and [3H]-YM09151-2 specific binding.

Dopamine receptor expression in human fetal forebrain (between 6 and 20 weeks of gestation) was measured using tissue-slice receptor autoradiography with the D1-like and D2-like antagonists [3H]-SCH23390 and [3H]-YM09151-2, respectively. Tissue sections were assayed in saturation studies and examined for age- and sex-related changes in Bmax. We made the following observations: (1) the ages at which D1- and D2-like receptors were first expressed in whole forebrain sections could be reliably identified but were not significantly different from one another (gestational age 65 days for D1- vs. 72 days for D2-like receptors); (2) age-related increases in both D1- and D2-like receptors were demonstrated in forebrain and, from the middle of the first to the middle of the second trimester, the Bmax for each ligand increased by an order of magnitude after the onset of the specific binding site's expression; (3) age-related increases in D1-like receptors, but not D2-like receptors, could be demonstrated in cortex; and, (4) in one case of trisomy 18, the Bmax for [3H]-SCH23390 was significantly elevated above the 95% confidence interval when compared to an age-regressed normal sample. Although D2-like receptor density significantly increased with age in forebrain, age-regressed changes in D2-like receptor expression in cortex and striatum did not reach statistical significance. Likewise, a comparison of the mean Bmax's by sex for both ligands in midgestational striatum failed to reach significance. These data corroborate the findings of other investigators who have delineated the ontogeny of dopaminergic systems in other animal species. The regional differences in the expression of dopamine receptor families may be relevant to the role which dopamine may play during normal gestational brain development. Moreover, significant deviations in dopamine receptor expression during gestation (as seen in this one case of trisomy 18) may signify underlying pathological processes that ultimately are manifested by abnormal psychological development and/or cognitive functioning.

NGFR-mRNA expression in sciatic nerve: a sensitive indicator of early stages of axonopathy.

Expression of the low-affinity nerve growth factor receptor (NGFR) in the sciatic nerve (particularly Schwann cells) is high during development but is downregulated upon establishment of the mature axon-Schwann cell relationship. NGFR is re-expressed by Schwann cells if this relationship is altered by degeneration of axons (axotomy) or myelin (tellurium intoxication). To determine the sensitivity of NGFR expression to axonal injury, we have assayed NGFR-mRNA levels in proximal and distal regions of nerves exposed to the axonopathic agents acrylamide and isoniazid, as well as in proximal and distal stumps of axotomized nerves. NGFR-mRNA was elevated in all three models and correlated regionally with sites of axonal perturbation. In distal regions of acrylamide- and isoniazid-intoxicated nerves, NGFR-mRNA was elevated at least 2 days prior to visible signs of axonal degeneration as assayed by morphological techniques utilizing light microscopy. NGFR-mRNA was also elevated in proximal regions of axotomized and acrylamide-intoxicated nerves prior to signs of axonal degeneration. In these models, increased mRNA expression correlated with alterations in the size distribution of axonal cross sections. The common response in all of these situations indicates that NGFR expression, in addition to being a marker for axonal degeneration, is also a sensitive indicator of less profound perturbations in normal axon-Schwann cell interactions, including early stages of axonopathy. We suggest that assay for NGFR-mRNA may be utilized as a rapid and simple method (relative to more labor-intensive morphological methods) to screen for peripheral neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurofilament and tubulin mRNA expression in Schwann cells.

Feeding of elemental tellurium to weanling rats blocks synthesis of cholesterol (a major component of myelin), and causes demyelination of the sciatic nerve. Expression of mRNA for myelin-specific genes in Schwann cells is downregulated. We now demonstrate specificity for Schwann cell injury in that expression of mRNAs for neurofilament subunits and for class II beta-tubulin (parameters sensitive to axonal injury) is unaltered in neurons of the dorsal root ganglia. An unexpected result was that in tellurium-treated rats there was marked upregulation of expression of mRNAs coding for the light and medium neurofilament subunits ("neuron-specific" proteins) as well as that for class II beta-tubulin (the major neuronal beta-tubulin isotype) in Schwann cells. Expression of these "neuronal" mRNA species was also detected in distal stumps of transected nerves at times when Schwann cells were undergoing dedifferentiation.

Primary demyelination induced by exposure to tellurium alters mRNA levels for nerve growth factor receptor, SCIP, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and myelin proteolipid protein in rat sciatic nerve.

Weanling rats fed a diet containing tellurium develop a peripheral neuropathy characterized by a highly synchronous primary demyelination; this demyelination is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis. Expression of mRNA for the major structural proteins of PNS myelin, myelin basic protein and P0, is coordinately down-regulated during the demyelinating phase and then up-regulated during the remyelinating phase (Toews et al., J. Neurosci. Res., 26 (1990) 501-507). We now report tellurium-induced alterations in gene expression for several proteins which are not major structural components of myelin in the peripheral nervous system. Expression of mRNA for nerve growth factor receptor in sciatic nerve was very low in control animals, but was markedly up-regulated after 3-5 days of exposure to tellurium, a time corresponding to the beginning of demyelination. Levels remained elevated during the subsequent period of remyelination. Expression of mRNA for SCIP (a presumptive transcription factor) was also up-regulated in sciatic nerve following tellurium exposure, with a time course similar to that for nerve growth factor receptor. When examined as a fraction of total RNA, steady-state mRNA levels for 2',3'-cyclic nucleotide 3'-phosphodiesterase and the myelin proteolipid protein were decreased during the demyelinating phase; however, this decrease could be largely accounted for by increased levels of total RNA. When analyzed on a 'per nerve' basis, steady-state mRNA levels for these two proteins were actually increased about 2-fold by 9 days after beginning tellurium exposure.(ABSTRACT TRUNCATED AT 250 WORDS)