Role of presynaptic input in the ontogeny of adrenergic cell signaling in rat brain: beta receptors, adenylate cyclase and c-fos protooncogene expression.
Neurotransmitters act as trophic factors during brain development, regulating expression of genes that control cellular differentiation. One example of this trophism is the beta adrenergic signaling cascade: activation of beta receptors leads sequentially to increased cyclic AMP (cAMP), augmented expression of the nuclear transcription factor, c-fos, and induction of ornithine decarboxylase (ODC), an enzyme obligatory for neuronal development. After neonatal lesioning of noradrenergic nerves with 6-hydroxydopamine (6-OHDA), beta receptors become uncoupled from ODC induction in the cerebellum, a region that undergoes its peak of cell replication/differentiation postnatally. The present study investigates the mechanism for uncoupling of beta receptors from response elements. In the cerebellum, 6-OHDA had minor effects on beta receptor binding capabilities and caused slight supersensitivity of the beta adrenergic response of adenylate cyclase; the latter reflected increased expression of cyclase catalytic subunits, rather than a specific effect on beta receptor coupling. In contrast, the linkage of cAMP to cerebellar c-fos expression showed marked deficiencies in lesioned animals and a corresponding loss of the ability of beta receptors to induce c-fos; accordingly, this is a likely point at which beta adrenergic control of ODC is programmed by neuronal input. A critical period exists for neurotrophic influence: the alterations persisted past the point at which cerebellar norepinephrine levels recovered, and comparable effects did not occur in earlier-developing regions. In the forebrain, for example, neonatal lesions produced receptor upregulation and supersensitivity of c-fos to cAMP stimulation. These results suggest that presynaptic input is vital in programming beta adrenergic responsiveness during a critical period of development, and that interruption of transsynaptic events occurring at this time can lead to lasting alterations in neuronal differentiation and responsiveness.
Wagner
J P
JP
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, USA.
Seidler
F J
FJ
Lappi
S E
SE
McCook
E C
EC
Slotkin
T A
TA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000502:physiology*; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D016762:Genes, fos; D007545:Isoproterenol / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D016627:Oxidopamine; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016627:Oxidopamine; D019204:GTP-Binding Proteins; D009955:Ornithine Decarboxylase; D000262:Adenylyl Cyclases; D007545:Isoproterenol