Lysophosphatidic acid stimulates neurotransmitter-like conductance changesthat precede GABA and L-glutamate in early, presumptive cortical neuroblasts

During neurogenesis in the embryonic cerebral cortex, the classical neurotr ansmitters GABA and L-glutamate stimulate ionic conductance changes in vent ricular zone (VZ) neuroblasts. Lysophosphatidic acid (LPA) is a bioactive p hospholipid producing myriad effects on cells including alterations in memb rane conductances (for review, see Moolenaar et at., 1995). Developmental e xpression patterns of its first cloned receptor gene, Ip(A1)/vzg-1 (Hecht e t al., 1996; Fukushima et al., 1998) in the VZ suggested that functional LP A receptors were synthesized at these early times, and thus, LPA could be a n earlier stimulus to VZ cells than the neurotransmitters GABA and L-glutam ate. To address this possibility, primary cultures of electrically coupled, presumptive cortical neuroblast clusters were identified by age, morpholog y, electrophysiological profile, BrdU incorporation, and nestin immunostain ing. Single cells from cortical neuroblast cell lines were also examined. W hole-cell variation of the patch-clamp technique was used to record from ne stin-immunoreactive cells after stimulation by local administration of liga nds. After initial plating at embryonic day 11 (E11), cells responded only to LPA but not to GABA or L-glutamate. Continued growth in culture for up t o 12 hr produced more LPA-responsive cells, but also a growing population o f GABA- or L-glutamate-responsive cells. Cultures from E12 embryos showed L PA as well as GABA and L-glutamate responses, with LPA-responsive cells sti ll representing a majority. Overall, >50% of cells responded to LPA with de polarization mediated by either chloride or nonselective cation conductance s. These data implicate LPA as the earliest reported extracellular stimulus of ionic conductance changes for cortical neuroblasts and provide evidence for LPA as a novel, physiological component in CNS development.