DIFFERENTIAL EFFECTS OF NEONATAL NOREPINEPHRINE LESIONS ON IMMEDIATE EARLY GENE EXPRESSION IN DEVELOPING AND ADULT RAT BRAIN

摘要

Arc, c-fos and zif268 are immediate early genes (IEGs) important for adult brain plasticity. The current study examines developmental expression of these IEGs and the effect of neonatal noradrenergic lesion on their expression in developing and mature brain. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a specific noradrenergic neurotoxin, was administered to rats on postnatal day (PND) 3 and in situ hybridization was used to assay Arc, c-fos and zif268 mRNA on PND 13, 25 and 60. In contrast to decreases in Arc, c-fos and zif268 expression produced by noradrenergic lesions of mature brain, lesions on PND3 yield a strikingly different effect. Neonatal lesions produce increases in c-fos and zif268 expression in specific frontal cortical layers on PND13, while Arc shows no change. These lesions lead to increases in zif268 expression in frontal cortical layers on PND 25, with no changes in c-fos or Arc expression, and on PND60 they produce a significant increase in c-fos expression in hippocampus with no significant changes in Arc or zif268 expression. RX821002, an A2AR antagonist, administered to control PND 60 animals produces elevations of Arc, zif268 and c-fos mRNAs. This response was eliminated in animals lesioned with DSP-4 on PND 3. These data indicate that norepinephrine regulation of IEG expression differs in developing and mature brain and that the loss of developmental norepinephrine leads to abnormally high postnatal IEG expression. Several studies have shown an important role for norepinephrine in brain development, including the regulation of synaptic densities and neuronal morphology. Our data support the idea that norepinephrine plays an important role during CNS development and that changes in noradrenergic signaling during development may have long lasting effects, potentially on learning and memory.