Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening

Boxing Li, Benjamin S. Suutari, Simón(e) D. Sun, Zhengyi Luo, Chuanchuan Wei, Nicolas Chenouard, Nataniel J. Mandelberg, Guoan Zhang, Brie Wamsley, Guoling Tian, Sandrine Sanchez, Sikun You, Lianyan Huang, Thomas A. Neubert, Gordon Fishell, Richard W. Tsien

Research output: Contribution to journalArticlepeer-review


Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca 2+-permeable AMPA receptor upregulation, L-type Ca 2+ channel activation, enhanced spine Ca 2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.

Original languageEnglish (US)
Pages (from-to)1547-1565.e15
Issue number7
StatePublished - Jun 25 2020


  • Alternative splicing
  • BK channel
  • CaM kinase
  • Nova-2
  • action potential duration
  • chronic inactivity
  • homeostasis
  • synaptic activity
  • Humans
  • Male
  • Calcium-Calmodulin-Dependent Protein Kinases/metabolism
  • Synapses/metabolism
  • Alternative Splicing/genetics
  • Nerve Tissue Proteins/metabolism
  • Large-Conductance Calcium-Activated Potassium Channels/genetics
  • HEK293 Cells
  • Neuronal Plasticity/physiology
  • Female
  • Long-Term Potentiation/physiology
  • Neuro-Oncological Ventral Antigen
  • Signal Transduction
  • Action Potentials/physiology
  • Homeostasis/physiology
  • Mice, Inbred C57BL
  • Rats
  • Rats, Sprague-Dawley
  • RNA-Binding Proteins/metabolism
  • Animals
  • Neurons/metabolism
  • Mice
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1/metabolism
  • Synaptic Transmission/physiology

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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