Patterned, spontaneous activity occurs in many developing neural circuits, including the retina, the cochlea, the spinal cord, the cerebellum and the hippocampus, where it provides signals that are important for the development of neurons and their connections. Despite differences in adult architecture and output across these various circuits, the patterns of spontaneous network activity and the mechanisms that generate it are remarkably similar and can include a depolarizing action of GABA, transient synaptic connections, extrasynaptic transmission, gap junction coupling and the presence of pacemaker-like neurons. Interestingly, spontaneous activity is robust; if one element of a circuit is disrupted another will generate similar activity. This research suggests that developing neural circuits exhibit transient and tunable features that maintain a source of correlated activity during critical stages of development.

Patterns of synaptic connections in the visual system are remarkably precise. These connections dictate the receptive field properties of individual visual neurons and ultimately determine the quality of visual perception. Spontaneous neural activity is necessary for the development of various receptive field properties and visual feature maps. In recent years, attention has shifted to understanding the mechanisms by which spontaneous activity in the developing retina, lateral geniculate nucleus, and visual cortex instruct the axonal and dendritic refinements that give rise to orderly connections in the visual system. Axon guidance cues and a growing list of other molecules, including immune system factors, have also recently been implicated in visual circuit wiring. A major goal now is to determine how these molecules cooperate with spontaneous and visually evoked activity to give rise to the circuits underlying precise receptive field tuning and orderly visual maps.

Highly correlated neural activity in the form of spontaneous waves of action potentials is present in the developing retina weeks before vision. Optical imaging revealed that these waves consist of spatially restricted domains of activity that form a mosaic pattern over the entire retinal ganglion cell layer. Whole-cell recordings indicate that wave generation requires synaptic activation of neuronal nicotinic acetylcholine receptors on ganglion cells. The only cholinergic cells in these immature retinas are a uniformly distributed bistratified population of amacrine cells, as assessed by antibodies to choline acetyltransferase. The results indicate that the major source of synaptic input to retinal ganglion cells is a system of cholinergic amacrine cells, whose activity is required for wave propagation in the developing retina.

Before phototransduction, spontaneous activity in the developing mammalian retina is required for the appropriate patterning of retinothalamic connections, and there is growing evidence that this activity influences the development of circuits within the retina itself. We demonstrate here that the neural substrate that generates waves in the mouse retina develops through three distinct stages. First, between embryonic day 16 and birth [postnatal day 0 (P0)], we observed both large, propagating waves inhibited by nicotinic acetylcholine receptor (nAChR) antagonists and small clusters of cells displaying nonpropagating, correlated calcium increases that were independent of nAChR activation. Second, between P0 and P11, we observed only larger propagating waves that were abolished by toxins specific to ␣3 and ␤2 subunit-containing nAChRs. Third, between P11 and P14 (eye opening) we observed propagating activity that was abolished by ionotropic glutamate receptor antagonists. The time course of this developmental shift was dramatically altered in retinas from mice lacking the ␤2 nAChR subunit or the ␤2 and ␤4 subunits.These retinas exhibited a novel circuit at P0, no spontaneous correlated activity between P1 and P8, and the premature induction at P8 of an ionotropic glutamate receptor-based circuit. Retinas from postnatal mice lacking the ␣3 nAChR subunit exhibited spontaneous, correlated activity patterns that were similar to those observed in embryonic wild-type mice. In ␣3Ϫ/Ϫ and ␤2Ϫ/Ϫ mice, the development and distribution of cholinergic neurons and processes and the density of retinal ganglion cells (RGCs) and the gross segregation of their dendrites into ON and OFF sublaminae were normal. However, the refinement of individual RGC dendrites is delayed. These results indicate that retinal waves mediated by nAChRs are involved in, but not required for, the development of neural circuits that define the ON and OFF sublamina of the inner plexiform layer.