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Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABA_A receptor (GABA_AR) conductance. The effects of GABA_AR activation depend on the intracellular Cl⁻ concentration ([Cl⁻]_i) that is determined by the inward Cl⁻ transporter NKCC1 and the outward Cl⁻ transporter KCC2. Differential maturation of Cl⁻ transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl⁻]_i and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl⁻]_i, and were excited by GABA_AR activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences …