GABA-induced motility of spinal neuroblasts develops along a ventrodorsal gradient and can be mimicked by agonists of GABAA and GABAB receptors.
During embryogenesis, neuroblasts proliferate within germinal zones, then migrate to their final positions. Although many neurons migrate along radial glial fibers, evidence suggests that environmental factors, as yet unidentified, also influence neuroblast movement. In vivo, nerve growth factor (NGF) and gamma-aminobutyric acid (GABA) colocalize near target destinations of migratory neuroblasts. In vitro, embryonic spinal neurons migrate towards NGF and GABA (Behar et al.: J Neurosci 14:29-38, 1994), implying that the molecules may act as chemoattractants in vivo. Here, we have used an in vitro assay of migration to show that migratory responses to these attractants develop along a ventrodorsal gradient that parallels terminal mitosis during cord development, and that GABA stimulates chemokinesis (motility without a gradient) via heterogeneous receptors involving separate signalling pathways. Both GABAA (muscimol) and GABAB (baclofen) agonists mimicked the effects of GABA in stimulating chemokinesis. Muscimol-induced motility was only blocked by GABAA antagonists (bicuculline or picrotoxin), whereas migration to baclofen was blocked by antagonists of both GABAA and GABAB (2-hydroxysaclofen) receptors. Migration to baclofen, but not muscimol, was abolished in the presence of 8-bromo cAMP or pertussis toxin, indicating that the former, but not the latter, attractant may stimulate motility via Gi/Go GTP binding proteins, and that PKA may modulate migratory responses to baclofen. Migration to GABA was partially attenuated by each of the GABA receptor antagonists. These results lead us to conclude that the natural ligand stimulates neuroblast motility via heterogeneous receptors coupled to different signalling mechanisms.
Laboratory of Neurophysiology, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
T N
TN
Behar
A E
AE
Schaffner
H T
HT
Tran
J L
JL
Barker
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001418:Baclofen / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009118:Muscimol / Q000494:pharmacology; D009473:Neuronal Plasticity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000196:embryology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen