GABA Type-A Activity Controls Its Own Developmental Polarity Switch in the Maturing Retina

In the developing CNS, GABAA responses switch from early excitation to late mature inhibition. The developmental factors that induce the polarity switch remain to be unraveled. Here, we bring the first experimental evidence in vivo in the retina that chronic activation of GABAA receptors is necessary for the switch to occur and for the chloride extrusion mechanism (through the K+/Cl- cotransporter KCC2) to develop. Using a turtle model and calcium imaging, we investigated how chronic blockade of GABAA receptors with bicuculline during the period of the GABAergic polarity switch (from 1 week before hatching until 4 weeks after hatching) influences developmental changes in the patterns of spontaneously generated electrical activity in the retinal ganglion cell (RGC) layer. During that period, spontaneous activity normally switches from propagating waves to stationary patches of coactive cells, until correlated activity completely disappears. These changes in activity patterns coincide with the switch of GABAA responses from excitation to inhibition. When GABAA receptors are chronically blocked, GABAA responses remain excitatory and spontaneous waves keep propagating across the RGC layer. Concomitantly, the developmental upregulation of KCC2 is inhibited on dendritic processes in the inner plexiform layer, suggesting that the intracellular concentration of chloride remains higher, as in younger cells. This study presents the first demonstration in vivo that GABA autoregulates its developmental polarity switch, emphasizing the importance of GABAergic activity in controlling activity patterns in the maturing retina.