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.
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Related Subject Headings
- Receptors, Adrenergic, beta
- Rats, Sprague-Dawley
- Rats
- Pregnancy
- Pharmacology & Pharmacy
- Oxidopamine
- Ornithine Decarboxylase
- Isoproterenol
- Genes, fos
- GTP-Binding Proteins
Citation
Published In
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Adrenergic, beta
- Rats, Sprague-Dawley
- Rats
- Pregnancy
- Pharmacology & Pharmacy
- Oxidopamine
- Ornithine Decarboxylase
- Isoproterenol
- Genes, fos
- GTP-Binding Proteins