Mechanisms of Circuit Plasticity in the Developing Retina

Across the developing nervous system, immature networks generate spontaneous activity that is highly correlated amongst neighboring cells, which is required for the correct establishment of adult neural circuits. Remarkably, correlated activity persists following disruption of the underlying circuits that mediate it, indicating that plasticity mechanisms exist to ensure correlated activity is maintained. Here, we examine this phenomenon in the developing mouse retina, where correlated activity is mediated by cholinergic transmission and propagates across the retina as a wave. The absence of cholinergic signaling leads to the generation of "recovered" waves that propagate through a distinct, gap junction mediated circuit. Our findings show that stimulation of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) facilitates recovery of correlated activity in the absence of cholinergic waves, which results in the emergence of a light-sensitive network. We tested whether pharmacological blockade of cholinergic waves altered retinal light-response properties. We observed an increase in the duration of light-evoked activity and number of light-responsive cells, which arose from signaling via gap junctions. These observations suggest that electrical coupling of ipRGCs increases in the absence of cholinergic input, allowing melanopsin-driven signals to propagate to other neurons. Furthermore, we show that light-sensitive waves are strongly modulated by dopamine signaling--a potent neuromodulator of gap junction coupling. We determine that this light-sensitive wave circuit is present but latent in wild type retina, where it is usually suppressed by a combination of cholinergic and dopaminergic signaling. Our observations indicate that dopamine signaling acts as a switch for network reconfiguration, where high dopamine silences the light-sensitive, gap junction coupled network under cholinergic waves and reduced dopamine activates it in the absence of cholinergic waves. We conclude that the wiring diagram of the developing retina includes several overconnected circuits, in which some circuits are closed and others activated depending on the internal state of the system