Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability

Jessica Di Re, Wei Chun J. Hsu, Cihan B. Kayasandik, Nickolas Fularczyk, T. F. James, Miroslav Nenov, Pooran Negi, Mate Marosi, Federico Scala, Saurabh Prasad, Demetrio Labate, Fernanda Laezza

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The axon initial segment (AIS) is a highly regulated subcellular domain required for neuronal firing. Changes in the AIS protein composition and distribution are a form of structural plasticity, which powerfully regulates neuronal activity and may underlie several neuropsychiatric and neurodegenerative disorders. Despite its physiological and pathophysiological relevance, the signaling pathways mediating AIS protein distribution are still poorly studied. Here, we used confocal imaging and whole-cell patch clamp electrophysiology in primary hippocampal neurons to study how AIS protein composition and neuronal firing varied in response to selected kinase inhibitors targeting the AKT/GSK3 pathway, which has previously been shown to phosphorylate AIS proteins. Image-based features representing the cellular pattern distribution of the voltage-gated Na+ (Nav) channel, ankyrin G, βIV spectrin, and the cell-adhesion molecule neurofascin were analyzed, revealing βIV spectrin as the most sensitive AIS protein to AKT/GSK3 pathway inhibition. Within this pathway, inhibition of AKT by triciribine has the greatest effect on βIV spectrin localization to the AIS and its subcellular distribution within neurons, a phenotype that Support Vector Machine classification was able to accurately distinguish from control. Treatment with triciribine also resulted in increased excitability in primary hippocampal neurons. Thus, perturbations to signaling mechanisms within the AKT pathway contribute to changes in βIV spectrin distribution and neuronal firing that may be associated with neuropsychiatric and neurodegenerative disorders.

Original languageEnglish (US)
Article number643860
JournalFrontiers in Molecular Neuroscience
StatePublished - Jun 30 2021


  • AIS plasticity
  • GSK3 – glycogen synthase kinase 3
  • WEE1 kinase
  • confocal imaging
  • patch clamp electrophysiology
  • support vector machine classification

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability'. Together they form a unique fingerprint.

Cite this