GSK3β modulates timing-dependent long-term depression through direct phosphorylation of Kv4.2 channels

Giuseppe Aceto, Agnese Re, Andrea Mattera, Lucia Leone, Claudia Colussi, Marco Rinaudo, Federico Scala, Katia Gironi, Saviana Antonella Barbati, Salvatore Fusco, Thomas Green, Fernanda Laezza, Marcello D'Ascenzo, Claudio Grassi

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Spike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K+ currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K+ currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K+ currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity.

Original languageEnglish (US)
Pages (from-to)1851-1865
Number of pages15
JournalCerebral Cortex
Volume29
Issue number5
DOIs
StatePublished - May 2019

Keywords

  • A-type K current
  • GSK3β
  • Kv4.2
  • Personalized medicine
  • Somatosensory cortex
  • Spike timing-dependent plasticity

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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  • Cite this

    Aceto, G., Re, A., Mattera, A., Leone, L., Colussi, C., Rinaudo, M., Scala, F., Gironi, K., Barbati, S. A., Fusco, S., Green, T., Laezza, F., D'Ascenzo, M., & Grassi, C. (2019). GSK3β modulates timing-dependent long-term depression through direct phosphorylation of Kv4.2 channels. Cerebral Cortex, 29(5), 1851-1865. https://doi.org/10.1093/cercor/bhy042