Abstract
The inhibitory neurotransmitter GABA evokes excitation in immature brain instead of inhibition in adult brain. Since GABAA receptor is a Cl− channel, such a developmental switch of GABA action between excitation (Cl− efflux) and inhibition (Cl− influx) would be induced by a shift of Cl− homeostasis generated by a dynamic balance shift of cation-Cl− cotransporters (Cl− importer, NKCC1, and exporter, KCC2) during development. The excitatory GABA actions may be involved in neural circuitry development, since reduction of [Cl−]i by inhibiting NKCC1 resulted in less formation of inhibitory synapse formation. High [Cl−]i and excitatory GABA actions may also contribute to neuronal cell migration, since migrating cells had the higher [Cl−]i, the higher expression of NKCC1 and the lower expression of KCC2 than already-settled cells, which were depolarized instead of hyperpolarized by GABA. Indeed, a blockade of GABAA receptors resulted in migration disorder. A conversion of the GABA response from inhibition to excitation was induced by injuries. In cortical freeze-lesion model, cells adjacent to the lesion site regained immature status of Cl− homeostasis and GABA actions, so that they anomalously migrated. In axotomized motoneurons, the increases in [Cl−]i induced by KCC2 downregulation turned GABAergic inhibition to excitation. The induced spontaneous [Ca2+]i oscillation might be related with re-wiring of afferent inputs. Such a downregulation of KCC2 also induced in postsynaptic neurons by the injury of primary afferents, suggesting functional dynamics of inhibitory pathway regulated by active changes in Cl− homeostasis. [J Physiol Sci. 2007;57 Suppl:S20]
