GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABAA receptor activation, calcium influx and CAMKII and erk1/2 pathways

Laura N Borodinsky, Deirdre O'Leary, Joseph H. Neale, Stefano Vicini, Omar A. Coso, Mönica L. Fiszman

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

During neuronal development, GABAA-mediated responses are depolarizing and induce an increase in the intracellular calcium concentration. Since calcium oscillations can modulate neurite outgrowth, we explored the capability of GABA to induce changes in cerebellar granule cell morphology. We find that treatment with GABA (1-1000 μm) induces an increase in the intracellular calcium concentration through the activation of GABAA receptors and voltage-gated calcium channels of the L-subtype. Perforated patch-clamp recordings reveal that this depolarizing response is due to a chloride reversal potential close to -35 mV. When cells are grown in depolarizing potassium chloride concentrations, a shift in reversal potential (Erev) for GABA is observed, and only 20% of the cells are depolarized by the neurotransmitter at day 5 in vitro, On the contrary, cells grown under resting conditions are depolarized after GABA application even at day 8. GABA increases the complexity of the dendritic arbors of cerebellar granule neurons via a calcium-dependent mechanism triggered by voltage-gated calcium channel activation. Specific blockers of calcium-calmodulin kinase II and mitogen-activated protein kinase kinase (KN93 and PD098059) implicate these kinases in the intracellular pathways involved in the neurotogenic effect of GABA. These data demonstrate that GABA exerts a stimulatory role on cerebellar granule cell neuritogenesis through calcium influx and activation of calcium-dependent kinases.

Original languageEnglish (US)
Pages (from-to)1411-1420
Number of pages10
JournalJournal of Neurochemistry
Volume84
Issue number6
DOIs
StatePublished - Mar 2003

Keywords

  • Calcium influx
  • CaMKII
  • Depolarization
  • Erk1/2
  • GABA receptors
  • Neuritogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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