Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord.
The development of nicotinic acetylcholine receptors (nAChRs) in brains from human fetuses of 4-12 weeks gestational age was studied. The expression of nAChR subunit mRNAs was analyzed using reverse transcriptase-polymerase chain reaction. Expression of alpha 3, alpha 4, alpha 5, alpha 7, beta 2, beta 3 and beta 4 mRNA were all detected in the prenatal spinal cord, medulla oblongata, pons, cerebellum, mesencephalon, subcortical forebrain and cortex during first trimester development. Relative quantification of mRNA showed that the highest levels for alpha 3, alpha 4 and alpha 7 were expressed in the spinal cord, alpha 5 was most abundant in the cortex and beta 3 was highest in the cerebellum. beta 4 seemed to be equally distributed in all regions whereas beta 2 was high in the cortex and cerebellum. A comparison of expression of nAChR subunit mRNAs in the cortex and cerebellum of prenatal and aged (54-81 years) brain showed that mRNA levels for alpha 4, alpha 5, alpha 7, beta 2 and beta 4 were significantly higher in the prenatal cortex and cerebellum than in aged brain, whereas the level of alpha 3 transcript was similar, and beta 3 significantly higher in aged cortex. Specific binding of [3H]-epibatidine to prenatal brain membranes was detected as early as 4-5 weeks of gestation in the spinal cord, medulla oblongata, pons and subcortical forebrain. A positive correlation between gestational age and [3H]-epibatidine and [3H]-cytisine binding was found in several brain regions. The highest specific binding of [3H]-epibatidine and [3H]-cytisine was detected in the spinal cord, pons and medulla oblongata and the lowest in the cortex. Saturation analysis of [3H]-cytisine binding in both prenatal and aged brain were best fit by a model for a single site, whereas binding data for [3H]-epibatidine revealed two classes of binding sites. The early presence of nAChR proteins and gene transcripts shown in the present study suggests an important role for nAChRs in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development.
Department of Clinical Neuroscience and Family Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden.
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E
Hellström-Lindahl
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Gorbounova
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A
Seiger
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M
Mousavi
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Nordberg
D000368:Aged; D000369:Aged, 80 and over; D000470:Alkaloids / Q000494:pharmacology; D001392:Azocines; D001921:Brain / Q000196:embryology*; D001923:Brain Chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D002531:Cerebellum / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D015342:DNA Probes; D005260:Female; D005333:Fetus / Q000737:chemistry; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008526:Medulla Oblongata / Q000737:chemistry; D008636:Mesencephalon / Q000737:chemistry; D008875:Middle Aged; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000032:analysis / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011149:Pons / Q000737:chemistry; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011807:Quinolizines; D012333:RNA, Messenger / Q000032:analysis; D012194:RNA-Directed DNA Polymerase; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000032:analysis / Q000235:genetics*; D013116:Spinal Cord / Q000737:chemistry* / Q000196:embryology*; D014316:Tritium; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015342:DNA Probes; D009538:Nicotine; D018722:Nicotinic Agonists; D019696:Peptidylprolyl Isomerase; D011725:Pyridines; D011807:Quinolizines; D012333:RNA, Messenger; D012194:RNA-Directed DNA Polymerase; D011978:Receptors, Nicotinic; D014316:Tritium; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine