Retinal waves drive calcium transients in undifferentiated retinal cells. Focus on "spontaneous waves in the ventricular zone of developing mammalian retina".

There is growing evidence that even before synapses form, spontaneous calcium transients can influence many aspects of neurodevelopment (Spitzer 2002). These early spontaneous calcium transients can be patterned both temporally as periodic oscillations and spatially as propagating waves or as synchronized events across neighboring cells. Two major questions in developmental neuroscience: how are these patterns generated, and what cellular processes are driven by these patterns? The first of these questions is addressed by Syed et al. (this issue, p. 1999–2009). They focus on the embryonic rabbit retina, where they show that undifferentiated cells in the ventricular zone undergo spontaneous, highly correlated calcium transients that take the form of propagating waves. Note, these waves are distinct from previously described retinal waves (Feller 2002; Zhou 2001) because they propagate through the ventricular zone and not amacrine and retinal ganglion cells. The retina develops in roughly a layer-by-layer manner. The inner retina (the cell layers closer to the vitreal surface) develops first when ganglion cells migrate to the ganglion cell layer and send their projections via the optic nerve to central brain structures. Ganglion cells then start to receive synaptic input from interneurons. At this stage, inner retinal waves (IR waves) emerge, involving amacrine cells and ganglion cells, and driving patterning of ganglion cell axons (Feller 2002). VZ waves occur during this same stage of development. Synchronous increases in intracellular calcium have been seen previously in ventricular zone of cortex (Owens and Kriegstein 1998) and chick retina (Catsicas et al. 1998); however, in neither case were such large propagating events observed. Syed et al. show that VZ and IR waves are strongly correlated spatially and temporally despite occurring in separate retinal layers. Also, VZ waves are blocked by all drugs that block IR waves, including gap junction antagonists. The strong correlation between VZ and IR waves begs the question of who is driving whom? The authors argue that VZ waves depend on IR waves because bath application of a muscarinic acetylcholine receptor (mAChR) antagonist blocks calcium transients in VZ waves but spares IR waves, which depend on activation of nicotinic but not muscarinic AChRs (Zhou 2001; Feller 2002). Interestingly, there is only one source of ACh in the retina—a subclass of interneurons called starburst amacrine cells. [Note, in some species, there is also transient expression on choline acetyltransferase in immature horizontal cells (Nguyen and Grzywncz 2000).] Thus the results here indicate that ACh released in the inner retina diffuses to the VZ to activate mAChRs. Consistent with this model of “volume transmission,” acetylcholine esterase inhibitors enhanced the time course of calcium transients induced by VZ waves. What is the function of these mAChR-driven waves in VZ cells? One possibility is that mAChRs play a unique role in signaling for undifferentiated cells. Consistent with this idea, young (E20) rabbit neuroblastic cells are responsive to mAChR agonists but lose this responsiveness when the cells become postmitotic and begin to migrate out of the ventricular zone (Wong 1995). A possible function of such signaling is suggested from work in chick retina, where activation of mAChRs can regulate the cell cycle (Pearson et al. 2002). How mAChRs exert this effect is unclear but may involve calcium signaling because mAChRs cause release from intracellular stores. Calcium signaling is also known to play a role in early phases of neurogenesis and cell migration (Spitzer 2002) including in cortical VZ cells (Owens and Kriegstein 1998). One possible function for correlated waves of calcium transients in the VZ therefore is to coordinate differentiation of groups of VZ cells that will form particular cell classes. This work represents a significant contribution in our understanding of how spontaneous neural signaling is generated in undifferentiated cells. The question remains how calcium transients are “decoded” and thereby influence early developmental events.