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L. Zhang, P. Sterling, N. Vardi; Reciprocal Expression of Cation Chloride Cotransporters (NKCC and KCC2) in Mouse Retina May Cause the Switch of GABA from Excitatory to Inhibitory . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2040.
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Purpose: In developing retina, GABA is initially excitatory and later becomes inhibitory. This switch is presumably caused by a shift in chloride equilibrium potential (Ecl). We investigated possible contributions to the shift in Ecl by the Na-K-Cl cotransporter (NKCC), which accumulates chloride, and the K-Cl cotransporter (KCC2), which extrudes chloride. Methods: Using developing mouse retina, we quantified the expression level of NKCC and KCC2 with immunostaining and Western blots, and also studied the effects of GABA and its antagonist, picrotoxin, with Fura-2 imaging. Results: NKCC was initially high in the inner plexiform and ganglion cell layers (P0-P5); then it declined rapidly (P6) and maintained a low level (adult). KCC2 was initially almost undetectable; then it increased significantly as NKCC declined. This reciprocal expression predicted that GABA would switch from excitatory to inhibitory at P6. Indeed, in P0-P5 mouse retinas, bath application of GABA evoked slow calcium rises in cells of the ganglion cell layer. These responses were blocked by coapplication of picrotoxin. In P6-P11 retinas, GABA evoked no calcium rise, but blocking GABAA/C receptor induced strong bursting activity from normally silent ganglion cells, suggesting that GABA had switched from excitatory to inhibitory. Conclusions: The reciprocal expression of NKCC and KCC2 may cause the switch of GABA from excitatory to inhibitory.
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