Fluoxetine induces restoration of plasticity in the adult vestibular system

Abstract

Antidepressant fluoxetine is known to restore neuronal plasticity in the adult visual cortex by modulating GABA level. We hypothesize that fluoxetine also reinstates plasticity in the adult vestibular nucleus (VN) by altering GABAergic transmission. We previously showed that derangement of spatial navigation in adult rats was observed with neonatal blockade of GABAA receptor (GABAAR) in the VN but not with blockade applied after P14. In the present study, we demonstrated that deficits in spatial navigation could still be induced in adult rats that received both bicuculline treatment in the VN and oral administration of fluoxetine from P21 onwards. This implies that fluoxetine restores the plasticity observed in critical period during which bicuculline induces deficits in spatial navigation. With western blot analysis, we found that oral administration of fluoxetine during P21–28 significantly reduced protein expression of potassium-chloride co-transporter (KCC2) in the VN. Since KCC2 is responsible for the extrusion of chloride ions, lower level of KCC2 expression indicates less chloride ions flowing through GABAAR, causing a reduction in the impact of inhibitory GABAergic transmission. The latter is corroborated with the observation that the proportion of VN neurons exhibiting GABAAR-mediated long-term depression (LTD) was significantly increased from 34.6% in controls to 50% in P28 rats pre-treated with fluoxetine during P21–28. These results imply that fluoxetine induces a reduction in GABAergic transmission, thus contributing to the restoration of the plasticity observed in critical period. [Supported by HKU 761812M].