, 2006, Cang et al., 2005, Rebsam et al., 2009 and Wang et al., 2009). However, these manipulations invariably change retinal activity levels in addition to disrupting retinal waves, making it ambiguous whether a threshold level of activity or specific patterns of spontaneous waves are important in map development. Moreover, genetic manipulations of spontaneous retinal waves have mainly utilized whole-animal knockouts (β2(KO) mice), leading to uncertainty about
the retinal origin of the observed visual map phenotypes because of the broad expression of β2-nAChRs in the eye and brain. Here, we establish an instructive role for spontaneous activity in neural circuit development by investigating the emergence of retinotopy and eye-specific segregation in a line of transgenic S3I 201 mice (β2(TG) mice) with β2-nAChR selleck chemicals llc expression that is limited to the ganglion cell layer of the retina. A detailed examination of spontaneous activity in β2(TG) mice shows that a wide range of single-neuron RGC activity parameters are normal, but the spatiotemporal pattern (spread) of retinal waves is visibly truncated. Remarkably, this retinal wave manipulation completely disrupts the segregation of eye-specific inputs to the dLGN and SC but has no influence on the
development of retinotopic maps in the monocular zone of the dLGN and SC. These results demonstrate that the presence of normal levels of spontaneous retinal activity, including bursts of spikes and even “small” retinal waves, is not sufficient to produce normal circuits. Rather, we identify specific spatiotemporal patterns of spontaneous retinal activity that are necessary for
the emergence of eye-specific segregation, and distinct aspects of retinal activity that mediate the development of retinotopy. This shows that spontaneous retinal waves are not just permissive but instructive in the development of the visual system and suggests that specific and distinct patterns of spontaneous activity found throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity. We examined the role of retinal β2-nAChRs and spontaneous waves in visual map development utilizing a line of transgenic mice with retina-specific expression of β2-nAChRs. Retinal specificity is achieved in these transgenic mice, referred to here as β2(TG) Resminostat mice, by expressing the tetracycline transactivator under control of the neuron-specific enolase promoter (NSE-tTA) and β2-nAChRs under the control of a tetracycline-regulated promoter (TetOp-β2) on a β2-null background ( Figures 1A and 1B; King et al., 2003). In this system ( Shockett et al., 1995), in the absence of tetracycline, tTA binds to a promoter consisting of the tetracycline operator (TetOp) to drive the expression of β2-nAChRs. When tetracycline is present, tTA undergoes a conformational change that interferes with binding to the TetOp promoter, and the transcription of β2-nAChRs is inhibited.