Neuron, Vol. 15, 1223-1225, December, 1995, Copyright 0 1995 by Cell Press The Usual Suspects: GABA and Glutamate May Regulate Proliferation in the Neocortex Minireview Anthony-Samuel LaMantia Department of Neurobiology Duke University Medical Center Durham, North Carolina 27710 In the film classic Casablanca, Claude Raines (playing the wry, slightly corrupt Chief Inspector of Police) exclaimed, “I am shocked” upon hearing of illicit behavior by agents within his jurisdiction. After years of evaluating the effects of many known mitogens, anti-mitogens, and other bona fide signaling molecules on neural precursor proliferation (reviewed by McConnell, 1991; Kilpatrick et al., 1995) it may come as a “shock” for many neurobiologists to read, in a paper by LoTurco and colleagues in this issue of Neu- ron, that y-aminobutyric acid (GABA) and glutamate-the ubiquitous inhibitory and excitatory neurotransmitters of the adult nervous system-can act as illicit (or at least unsuspected) anti-mitogens to regulate cortical neuro- genesis. One of the great unsolved mysteries of neocortical de- velopment is how precursor cells in the rudimentary corti- cal mantle exit the cell cycle in an orderly fashion and become destined for distinct laminar, regional, and func- tional fates in the mature cortex. From the time that PH]thymidine birthdating studies showed that neural pre- cursors whose progeny are destined for different cortical layers have different times of final cell division (Angevine and Sidman, 1961; Rakic, 1974) through current observa- tions of cellular and molecular asymmetry in the specifica- tion of cell division and fate in the cortical ventricular zone (Chenn and McConnell, 1995) it has been clear that a cortical precursor’s final exit from the cell cycle is a care- fully orchestrated event, most probably elicited by outside agents. This singular event has an impact upon the subse- quent migratory behavior of nascent cortical neurons, their laminar destination, and, perhaps, their ultimate cellular identity. As,demonstrated by LoTurco et al., GABA and glutamate can elicit depolarizing currents in cells from the ventricular zone of the embryonic rat neocortex, and both can also cause a decrease in DNA synthesis in the ventric- ular zone in vitro. These results make an intriguing, but still circumstantial, case that these two amino acids have the opportunity and the means to influence a neural pre- cursors exit from the cell cycle during the initial generation of the neocortical mantle. It has been known for almost a decade that GABAergic cells and processes (as well as several other neurotrans- mitter-containing processes) can be found suspiciously close to the ventricular zone (Lauder et al., 1966; Parna- velas and Cavanagh, 1966). Furthermore, immature cellu- lar contacts have been described between dividing precur- sor cells in the ventricular zone and a variety of other cellular processes (Stensaas and Stensaas, 1966). More importantly, cells in the ventricular zone appear to be com- petent to respond to GABAergic and glutamatergic sig- nals. They express several GABAA receptor isoforms (Lau- rie et al., 1992) and at least one kainate receptor subunit of theglutamate receptorfamily(Herbet al., 1992). Conse- quently, shock at this intriguing news of antimitotic and perhaps physiological actions for GABA and glutamate on proliferative cells in the neocortical ventricular zone might be slightly disingenuous. Clearly, neural precursor cells in the developing cortical mantle have access to cellular and molecular machinery that might allow them to receive and respond to GABAergic and glutamatergic signals (Fig- ure 1). The effects of GABA and glutamate on cortical neural precursors proposed by Lo Turco et al. join a fairly long list of physiological and cell biological consequences of neurotransmitter signaling in the developing central ner- vous system. GABA, glutamate, and their pharmacologi- cal agonists and antagonists have been long suggested to have toxic effects on the developing nervous system. Furthermore, both of these neurotransmitters can influ- ence several essential aspects of neuronal maturation in vitro and in vivo. GABA and glutamate have been shown to influence neuronal survival, growth cone pathfinding, and neuroblast movement, including migration on radial glia (Lipton and Kater, 1969; Komuro and Rakic, 1993; Behar et al., 1994). One assumption, rarely tested using the rigorous physiological and pharmacological assays employed by LoTurco et al., has been that during develop- ment these neurotransmitters act through their known re- ceptors to cause postsynaptic depolarizing or hyperpolar- izing responses much like those in adult neurons. This mechanism provides an appealing link between activity and signaling during the intermediate phases of regional, cellular, and circuit development in the cerebral cortex. LoTurco et al. show that both GABA and glutamate can influence conductances in ventricular zone cells via GA- BAA- and AMPAlkainate-type receptors (but not the NMDA-type!), respectively. The pharmacology of the re- sponses is consistent with the identification of these two ligand-receptor pairings. At first, the depolarizing, rather than hyperpolarizing, influence of GABA may seem myste- rious. Young neurons (and perhaps neural precursors) might have somewhat higher internal Cl- concentrations, and this difference could account for the currents seen in ventricular zone cells in response to GABA. Despite some lingering questions about the mechanism through which GABA and glutamate act, the circumstantial evidence is compelling enough: the receptors are there, the conduc- tances change, and in response to either GABA or gluta- mate in vitro, DNA synthesis is apparently diminished. The authors suggest that these two transmitters may arrest the cell cycle at the Gl to S phase. They do not, however, establish firmly the identity of the responsive cells in the ventricular zone, nor do they suggest whether this signal- ing is synaptic (thus dependent on cell-cell contact) or neurohumoral (thus less constrained spatially). Several other questions remain. Are the depolarizing currents re- ally from dividing neural precursor cells in the ventricular zone? Does the correlation between DNA synthesis and