Inhibition of constitutive inward rectifier currents in cerebellar granule cells by pharmacological and synaptic activation of GABAB receptors

Paola Rossi, Lisa Mapelli, Leda Roggeri, David Gall, Alban De Kerchove D'Exaerde, Serge N. Schiffmann, Vanni Taglietti, Egidio D'Angelo

Research output: Contribution to journalArticlepeer-review

Abstract

γ-Aminobutyric acid (GABA)B receptors are known to enhance activation of Kir3 channels generating G-protein-dependent inward rectifier K+-currents (GIRK). In some neurons, GABAB receptors either cause a tonic GIRK activation or generate a late K+-dependent inhibitory postsynaptic current component. However, other neurons express Kir2 channels, which generate a constitutive inward rectifier K+-current (CIRK) without requiring G-protein activation. The functional coupling of CIRK with GABAB receptors remained unexplored so far. About 50% of rat cerebellar granule cells in the internal granular layer of P19-26 rats showed a sizeable CIRK current. Here, we have investigated CIRK current regulation by GABAB receptors in cerebellar granule cells, which undergo GABAergic inhibition through Golgi cells. By using patch-clamp recording techniques and single-cell reverse transcriptase-polymerase chain reaction in acute cerebellar slices, we show that granule cells co-express Kir2 channels and GABAB receptors. CIRK current biophysical properties were compatible with Kir2 but not Kir3 channels, and could be inhibited by the GABAB receptor agonist baclofen. The action of baclofen was prevented by the GABAB receptor blocker CGP35348, involved a pertussis toxin-insensitive G-protein-mediated pathway, and required protein phosphatases inhibited by okadaic acid. GABAB receptor-dependent CIRK current inhibition could also be induced by repetitive GABAergic transmission at frequencies higher than the basal autorhythmic discharge of Golgi cells. These results suggest therefore that GABAB receptors can exert an inhibitory control over CIRK currents mediated by Kir2 channels. CIRK inhibition was associated with an increased input resistance around rest and caused a ∼5 mV membrane depolarization. The pro-excitatory action of these effects at an inhibitory synapse may have an homeostatic role reestablishing granule cell readiness under conditions of strong inhibition.

Original languageEnglish
Pages (from-to)419-432
Number of pages14
JournalEuropean Journal of Neuroscience
Volume24
Issue number2
DOIs
Publication statusPublished - Jul 2006

Keywords

  • Cerebellum
  • GABA receptors
  • Granule cells
  • Inward rectifier
  • Non-synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

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