Developmental Regulation of inhibitory neuronal circuits by neural activity

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The regulatory mechanisms of intracellular Cl-concentration ([Cl-] i ) were investigated in the lateral superior olive (LSO) neurons of various developmental stages by taking advantage of gramicidin perforated patch recording mode which enables neuronal [Cl-] i measurement. Responses to glycine changed from depolarization to hyperpolarization during the second week after birth, resulting from [Cl-] i decrease. Furosemide equally altered the [Cl-] i of both immature and mature LSO neurons, indicating substantial contributions of furosemide-sensitive intracellular Cl- regulators ; i.e. K+-Cl- cotransporter (KCC) and Na+-K+-Cl- cotransporter (NKCC), throughout this early development. Increase of extracellular K+ concentration and replacement of intracellular K+ with Cs+ resulted in [Cl-] i elevation at postnatal day (P) 13-15, but not at P0-2, indicating that the mechanism of neuronal Cl- extrusion is sensitive to both furosemide and K+-gradient, and poorly developed in immature LSO neurons. In addition, removal of extracellular Na+ decreased [Cl-] i at P0-2, suggesting the existence of extracellular Na+- dependent and furosemide-sensitive Cl-accumulation in immature LSO neurons. These data show clearly that developmental changes of Cl--cotransporters alter [Cl-] i and are responsible for the switch from the neonatal Cl- efflux to the mature Cl- influx in LSO neurons. Such maturational changes in Cl--cotransporters might have the important functional roles for glycinergic and GABAergic synaptic transmission and the broader implications for LSO and auditory development.