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Shift of Intracellular Chloride Concentration in Ganglion and Amacrine Cells of Developing Mouse Retina

¹Department of Neuroscience, University of Pennsylvania School of Medicine; and ²Division of Neurology, Pediatric Regional Epilepsy Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Submitted 3 June 2005; accepted in final form 19 December 2005

GABA and glycine provide excitatory action during early development: they depolarize neurons and increase intracellular calcium concentration. As neurons mature, GABA and glycine become inhibitory. This switch from excitation to inhibition is thought to result from a shift of intracellular chloride concentration ([Cl^–]_i) from high to low, but in retina, measurements of [Cl^–]_i or chloride equilibrium potential (E_Cl) during development have not been made. Using the developing mouse retina, we systematically measured [Cl^–]_i in parallel with GABA's actions on calcium and chloride. In ganglion and amacrine cells, fura-2 imaging showed that before postnatal day (P) 6, exogenous GABA, acting via ionotropic GABA receptors, evoked calcium rise, which persisted in HCO₃^–- free buffer but was blocked with 0 extracellular calcium. After P6, GABA switched to inhibiting spontaneous calcium transients. Concomitant with this switch we observed the following: 6-methoxy-N-ethylquinolinium iodide (MEQ) chloride imaging showed that GABA caused an efflux of chloride before P6 and an influx afterward; gramicidin-perforated-patch recordings showed that the reversal potential for GABA decreased from –45 mV, near threshold for voltage-activated calcium channel, to –60 mV, near resting potential; MEQ imaging showed that [Cl^–]_i shifted steeply around P6 from 29 to 14 mM, corresponding to a decline of E_Cl from –39 to –58 mV. We also show that GABAergic amacrine cells became stratified by P4, potentially allowing GABA's excitatory action to shape circuit connectivity. Our results support the hypothesis that a shift from high [Cl^–]_i to low causes GABA to switch from excitatory to inhibitory.

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