Control of neuronal nitric oxide synthase and brain-derived neurotrophic factor levels by GABA-A receptors in the developing rat cortex.
Gamma-aminobutyric acid (GABA) plays an important morphogenetic role, acting through GABA-A receptors, which are depolarizing in the developing rat brain. Other molecules with major morphogenetic roles are the nitric oxide free radical (NO(.)) and brain-derived neurotrophic factor (BDNF), both of which are involved in the control of synaptic plasticity and apoptosis. In the present work, we investigated the effect of GABA-A receptor activation on neuronal NO(.) synthase (nNOS) and BDNF immunoreactivity in the developing cortex of 5-day-old rats. We also determined the effect of GABA-A receptor activation on phosphorylated cAMP-response element binding protein (pCREB) immunoreactivity in an effort to elucidate the molecular mechanisms involved. Our results show that activation of GABA-A receptors leads to increased numbers of nNOS, BDNF and pCREB, as well as nNOS-pCREB and BDNF-pCREB doubly immunopositive cells. This effect is abolished when L-type Ca(2+) channels are blocked. These results indicate that the following mechanism could be operating: depolarization following GABA-A receptor activation leads to opening of L-type voltage-gated calcium channels, resulting in an increased Ca(2+) influx, which in turn leads to phosphorylation and, thus, activation, of the transcription factor CREB; the phosphorylated CREB can then induce BDNF, as well as nNOS.
Mantelas
A
A
Laboratory of Biology--Biochemistry, School of Health Sciences, University of Athens, Papadiamantopoulou 123, Athens 11527, Greece.
Stamatakis
A
A
Kazanis
I
I
Philippidis
H
H
Stylianopoulou
F
F
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D003975:Diazepam