Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity, and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets, and sex selectivity.
Glucocorticoids administered to prevent respiratory distress in preterm infants are associated with neurodevelopmental disorders. To evaluate the long-term effects on forebrain development, we treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17-19, postnatal days 1-3, or postnatal days 7-9. In adulthood, we assessed biomarkers of neural cell number and size, cholinergic presynaptic activity, neurotransmitter receptor expression, and synaptic signaling mediated through adenylyl cyclase (AC), in the cerebral cortex, hippocampus, and striatum. Even at doses that were devoid of lasting effects on somatic growth, Dex elicited deficits in the number and size of neural cells, with the largest effect in the cerebral cortex. Indices of cholinergic synaptic function (choline acetyltransferase, hemicholinium-3 binding) indicated substantial hyperactivity in males, especially in the hippocampus, effectively eliminating the normal sex differences for these parameters. However, the largest effects were seen for cerebrocortical cell signaling mediated by AC, where Dex treatment markedly elevated overall activity while obtunding the function of G-protein-coupled catecholaminergic or cholinergic receptors that stimulate or inhibit AC; uncoupling was noted despite receptor upregulation. Again, the effects on signaling were larger in males and offset the normal sex differences in AC. These results indicate that, during critical developmental periods, Dex administration evokes lasting alterations in neural cell numbers and synaptic function in forebrain regions, even at doses below those used in preterm infants.
Kreider
Marisa L
ML
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Tate
Charlotte A
CA
Cousins
Mandy M
MM
Oliver
Colleen A
CA
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006426:Hemicholinium 3 / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000378:metabolism; D011247:Pregnancy; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D002395:Catecholamines; D014179:Neurotransmitter Uptake Inhibitors; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D006426:Hemicholinium 3; D003907:Dexamethasone; D002795:Choline O-Acetyltransferase; D000262:Adenylyl Cyclases