Long-lasting CNS effects of a short-term chemical knockout of ornithine decarboxylase during development: nicotinic cholinergic receptor upregulation and subtle macromolecular changes in adulthood.
Ornithine decarboxylase (ODC) and the polyamines play an essential role in brain cell replication and differentiation and polyamines also regulate the function of nicotinic acetylcholine receptors (nAChRs). We administered alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to neonatal rats on postnatal days 5-12, during the mitotic peak of the cerebellum, a treatment regimen that achieves a chemical knockout of ODC activity and polyamine depletion limited to the treatment period. Although growth inhibition and gross dysmorphology were limited to the cerebellum, both alpha7 and alpha4beta2 nAChRs were upregulated in adulthood in the frontal cortex, hippocampus and thalamus, with the largest effect in the latter region, primarily in females. Receptor upregulation was accompanied by abnormalities in macromolecular indices of cell packing density and cell membrane surface area, but the generalized cellular alterations did not share the regional or sex selectivity shown by the effects on nAChRs. Elevated DNA concentration was most notable in the hippocampus and was associated with augmented levels of glial fibrillary acidic protein, thus implying gliosis as the cause of the increased number of cells. DFMO's effects on both nAChR expression and cellular biomarkers resembled those of developmental exposure to nicotine. Accordingly, some of the effects may represent a specific alteration in nAChR signaling evoked by polyamine depletion during a critical developmental window. Alterations in polyamine gating of cholinergic synaptic signaling may thus contribute to the adverse neurobehavioral effects of numerous neuroteratogens that directly or indirectly disrupt the ODC/polyamine pathway.
Slotkin
Theodore A
TA
Department of Pharmacology & Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Freibaum
Brian D
BD
Tate
Charlotte A
CA
Thillai
Indira
I
Ferguson
Sherry A
SA
Cada
Amy M
AM
Seidler
Frederic J
FJ
D000818:Animals; D000831:Animals, Newborn; D002490:Central Nervous System / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D046911:Macromolecular Substances; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000172:deficiency / Q000378:metabolism*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000145:classification / Q000378:metabolism*; D012727:Sex Characteristics; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D008565:Membrane Proteins; D011978:Receptors, Nicotinic; D004247:DNA; D009955:Ornithine Decarboxylase; D000518:Eflornithine