Neonatal perturbation of KCC2 and NKCC1 co-transporters in the developing vestibular nucleus impairs vestibular functions

Abstract

The neurotransmitter GABA elicits depolarizing and hyperpolarizing synaptic response in immature and mature neurons, respectively. The polarity of GABA-mediated response is known to be mediated by two electroneutral co-transporters, namely NKCC1 and KCC2, which exhibit developmental shift in expression, phosphorylation and oligomerization levels. In the hippocampus, immature neurons contain primarily NKCC1, whereas mature neurons express KCC2 predominantly. We therefore hypothesize that NKCC1 and KCC2 modulate the maturation of vestibular functions at the behavioral level. With the use of immunohistochemistry, we showed that NKCC1 expression was restricted to early postnatal stage (P4 - P7), whereas KCC2 was expressed in the rat vestibular nucleus (VN) throughout postnatal development. Gramicidin-perforated patch-clamp experiments indicated that GABAA receptor-mediated response of neurons in the medial VN was depolarizing at P4, but then became hyperpolarizing at P14. Neonatal treatment of the VN with the implantation of Elvax slice loaded with NKCC1 blocker impaired labyrinthine righting in early postnatal days, whereas KCC2 blocker-treated rats showed a delay in the emergence of graviception (as indicated by the negative geotaxis test). The rats in the latter group when raised to adulthood showed impairment in spatial navigation (as indicated by the dead reckoning test). To conclude, the development of vestibular-related behaviors is dependent on the sequential activities of the two co-transporters which regulate the polarity of GABA-mediated response in the VN. [Supported by RGC Grants HKU761812, HKU762313]