MicroRNA-92 modulates K(+) Cl(-) co-transporter KCC2 expression in cerebellar granule neurons

Christian Barbato, Francesca Ruberti, Massimo Pieri, Elisa Vilardo, Manuela Costanzo, Maria Teresa Ciotti, Cristina Zona, Carlo Cogoni

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs have been associated to fine-tuning spatial and temporal control of gene expression during neuronal development. The neuronal Cl(-) extruding, K(+)Cl(-) co-transporter 2 (KCC2) is known to play an important role in neuronal Cl(-) homeostasis and in determining the physiological response to activation of anion selective GABA receptors. Here we show that microRNA-92 is developmentally down-regulated during maturation of rat cerebellar granule neurons (CGNs) in vitro. Computational predictions suggest several high-ranking targets for microRNA-92 including the KCC2 gene. Consistently, the KCC2 protein levels were up-regulated in mature CGN in vitro and a functional association between microRNA-92 and KCC2 3′ untranslated region was established using luciferase assays. The generation of an inward directed Cl(-) electrochemical gradient, necessary for the hyperpolarizing effect of GABA, requires robust KCC2 expression in several neuronal types. Here we show that lentiviral-mediated microRNA-92 over-expression reduced KCC2 protein levels and positively shifted reversal potential of GABA induced Cl(-) currents in CGNs. In addition KCC2 re-expression reversed microRNA-92 electrophysiological phenotype. Consistently microRNA-92 inhibition induced both an increase of the level of KCC2 and a negative shift in GABA reversal potential. These findings introduce a new player in the developmental change of GABA from depolarization to hyperpolarization.

Original languageEnglish
Pages (from-to)591-600
Number of pages10
JournalJournal of Neurochemistry
Volume113
Issue number3
DOIs
Publication statusPublished - May 2010

Keywords

  • Cerebellar granule neurons
  • Development
  • GABA
  • KCC2
  • MicroRNA

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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