Developmental switch of GABAergic signaling in starburst amacrine cells driven by chloride transporter dynamics

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During early postnatal development, γ-aminobutyric acid (GABA) signaling undergoes a functional switch from excitation to inhibition, driven by age-dependent shifts in intracellular chloride concentrations ([Cl⁻] i ).In the retina, starburst amacrine cells (SACs) are pivotal for establishing direction-selective circuitry.However, the molecular mechanisms and the precise timing of the reversal potential of GABA-induced currents (E GABA ) shift in mouse SACs remain to be fully elucidated.We investigated the maturation of GABA responsiveness and chloride homeostasis in mouse SACs during the neonatal period.Ca 2+ imaging in dissociated retinal neurons revealed that the application of GABA markedly increased intracellular Ca 2+ concentrations in SACs on postnatal day (P) 0-P2, whereas these excitatory responses were largely absent by P7-P9.Gramicidin-perforated patch recordings showed that E GABA underwent a significant hyperpolarizing shift with development, accompanied by a marked decrease in [Cl⁻] i .Immunohistochemical analyses demonstrated a developmental decline in Na + -K + -2Cl⁻ co-transporter (NKCC1) expression and the concomitant up-regulation of K + -Cl⁻ cotransporter (KCC2) in SACs.Consistent with these expression patterns, the pharmacological inhibition of NKCC1 or KCC2 selectively changed E GABA in a stagedependent manner.Collectively, these results demonstrate a developmentally regulated GABAergic switch in SACs orchestrated by coordinated changes in chloride transporter expression, providing insights into the physiological maturation of the retinal circuitry underlying direction selectivity.Highlights  GABA signaling in SACs shifts from excitatory to inhibitory during development. E GABA hyperpolarizes with age due to a marked decrease in [Cl⁻] i . Reciprocal NKCC1 and KCC2 regulation drives chloride dynamics in maturing SACs. These shifts provide a mechanistic basis for retinal circuitry maturation.

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