GABA: exciting again in its own right.

Which signals make a precursor cell become a neuron? Once identified, will we be able to use those signals to amplify certain types of neurons and direct them to areas where they are needed? While many extrinsic and intrinsic control pathways have been elucidated, it appears that one major mechanism occurs via neural progenitor depolarization by amino acid neurotransmitters. It is well established that the resting membrane potential of glial and neuronal progenitors can be modified by the activation of ligand-gated ionic channels before cells reach their final anatomical destination and differentiate. Among the extrasynaptic signals that can activate these membrane channels, the neurotransmitter γ-aminobutyric acid (GABA) has attracted considerable attention for two main reasons. First, the nature of the GABA-mediated response in neural cells changes during development. In embryonic and neonatal neurons, GABA provides an excitatory drive, whereas in the adult brain GABA is inhibitory (reviewed in Ben-Ari, 2002; Owens & Kriegstein, 2002). This is due to significant changes in [Cl−]i that occur as a consequence of nascent expression of the Na+,K+,Cl−-cotransporter around the end of the first postnatal week (Ben-Ari, 2002; Owens & Kriegstein, 2002). Second, GABA alters the proliferation and migration kinetics of prenatal neuronal progenitors (Behar et al. 1998; Owens & Kriegstein, 2002), and exerts trophic effects on neurons, promoting neurite outgrowth and synapse formation (reviewed in Ben-Ari, 2002; Owens & Kriegstein, 2002). In the postnatal brain, the subventricular zone (SVZ) and the rostral migratory stream (RMS) are the major areas exhibiting simultaneous proliferation and migration of progenitors and newly minted neurons. In an article in this issue of The Journal of Physiology, Wang et al. demonstrate that dividing neuronal progenitors in the SVZ and RMS synthesize GABA and are depolarized through the activation of GABA-gated ionic channels. The electrophysiological and anatomical analysis was conducted using a tissue slice preparation that maintained a relatively intact anatomical structure, preserving interactions between neighbouring cells. These findings invite the question as to the functional role of GABA-mediated depolarization in postnatal cells. Recent descriptions of GABA-induced modulation of prenatal progenitors may inform us as to the role of GABA in postnatal progenitor cells. Prenatal progenitor responses to amino acid neurotransmitters elucidate rapid intrinsic differentiation steps; more primitive VZ cells respond to GABA by increasing proliferation, while later-generated SVZ progenitors respond by proliferating more slowly (Haydar et al. 2000). Similar to the findings in the prenatal studies, Wang et al. (2003) report that expression of functional GABAA receptor channels is detectable when postnatal progenitors are still far from displaying action potentials and becoming synaptically integrated. In a recent patch-clamp study of migrating adult olfactory bulb neurons, Carleton et al. (2003) detected GABAA receptor-mediated depolarizing responses in immature neurons, well before spontaneous synaptic and spiking activities had developed. Thus, like prenatal progenitors, precursors and newly generated neurons in the postnatal and adult brain acquire physiological properties in a specific temporal sequence. It appears that expression of functional ligand-gated channels in neuronal progenitors and the cellular response initiated after their activation are part of an intrinsic programme which is independent of the formation of synaptic connections. As suggested by the prenatal studies, this intrinsic programme could serve to modulate proliferation and migration during postnatal progenitor amplification. While cells proliferate in transit from the SVZ through the RMS to the olfactory bulb, a balance between proliferation and migration must exist for proper numbers and timely ingress of new neurons. If the postnatal SVZ cells respond to GABA like their prenatal cousins, GABA should inhibit proliferation and promote migration. Thus, the proper ‘GABA tone’ may be required for balancing progenitor amplification and mobilization. The resurgence of interest in GABA-mediated signalling in neuronal progenitors during pre- and postnatal development opens fascinating avenues for future research. To further investigate the functional role of this transmitter and its receptors in postnatal and adult neurogenesis, the subunit composition of GABA-activated channels in neuronal progenitors will have to be determined. Then, GABA responses could be modified by using gain- and loss-of-function strategies, testing the hypothesis that targeted molecular perturbations of specific GABA receptor subunits will affect neuronal precursor development. In vivo electroporation of dominant negative subunits, or targeted mutations in the neuronal progenitor populations combined with live imaging, will define whether GABA-induced depolarization affects cell proliferation and/or migration. Another area of future exploration relates to the finding that SVZ neuronal progenitors themselves synthesize and store GABA. It will be important to define whether this neurotransmitter is released by neuronal precursors in a targeted fashion, as in a synapse, or as a paracrine signal. Altogether, recent advances describing the role of GABA depolarization in neuronal progenitor development could lead to novel strategies for repair and repopulation of the damaged and aging brain.