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

doi:10.1016/j.cell.2020.05.013

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

Center for Genomics and Systems Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English (US)
Pages (from-to)	1547-1565.e15
Journal	Cell
Volume	181
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2020.05.013
State	Published - Jun 25 2020

Keywords

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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10.1016/j.cell.2020.05.013

Cite this

Li, B., Suutari, B. S., Sun, S. D., Luo, Z., Wei, C., Chenouard, N., Mandelberg, N. J., Zhang, G., Wamsley, B., Tian, G., Sanchez, S., You, S., Huang, L., Neubert, T. A., Fishell, G., & Tsien, R. W. (2020). Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening. Cell, 181(7), 1547-1565.e15. https://doi.org/10.1016/j.cell.2020.05.013

Li, B, Suutari, BS, Sun, SD, Luo, Z, Wei, C, Chenouard, N, Mandelberg, NJ, Zhang, G, Wamsley, B, Tian, G, Sanchez, S, You, S, Huang, L, Neubert, TA, Fishell, G & Tsien, RW 2020, 'Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening', Cell, vol. 181, no. 7, pp. 1547-1565.e15. https://doi.org/10.1016/j.cell.2020.05.013

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

abstract = "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. ",

keywords = "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",

author = "Boxing Li and Suutari, {Benjamin S.} and Sun, {Sim{\'o}n(e) D.} and Zhengyi Luo and Chuanchuan Wei and Nicolas Chenouard and Mandelberg, {Nataniel J.} and Guoan Zhang and Brie Wamsley and Guoling Tian and Sandrine Sanchez and Sikun You and Lianyan Huang and Neubert, {Thomas A.} and Gordon Fishell and Tsien, {Richard W.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

day = "25",

doi = "10.1016/j.cell.2020.05.013",

language = "English (US)",

volume = "181",

pages = "1547--1565.e15",

journal = "Cell",

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TY - JOUR

T1 - Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening

AU - Li, Boxing

AU - Suutari, Benjamin S.

AU - Sun, Simón(e) D.

AU - Luo, Zhengyi

AU - Wei, Chuanchuan

AU - Chenouard, Nicolas

AU - Mandelberg, Nataniel J.

AU - Zhang, Guoan

AU - Wamsley, Brie

AU - Tian, Guoling

AU - Sanchez, Sandrine

AU - You, Sikun

AU - Huang, Lianyan

AU - Neubert, Thomas A.

AU - Fishell, Gordon

AU - Tsien, Richard W.

PY - 2020/6/25

Y1 - 2020/6/25

N2 - 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.

AB - 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.

KW - Alternative splicing

KW - BK channel

KW - CaM kinase

KW - Nova-2

KW - action potential duration

KW - chronic inactivity

KW - homeostasis

KW - synaptic activity

KW - Humans

KW - Male

KW - Calcium-Calmodulin-Dependent Protein Kinases/metabolism

KW - Synapses/metabolism

KW - Alternative Splicing/genetics

KW - Nerve Tissue Proteins/metabolism

KW - Large-Conductance Calcium-Activated Potassium Channels/genetics

KW - HEK293 Cells

KW - Neuronal Plasticity/physiology

KW - Female

KW - Long-Term Potentiation/physiology

KW - Neuro-Oncological Ventral Antigen

KW - Signal Transduction

KW - Action Potentials/physiology

KW - Homeostasis/physiology

KW - Mice, Inbred C57BL

KW - Rats

KW - Rats, Sprague-Dawley

KW - RNA-Binding Proteins/metabolism

KW - Animals

KW - Neurons/metabolism

KW - Mice

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 1/metabolism

KW - Synaptic Transmission/physiology

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U2 - 10.1016/j.cell.2020.05.013

DO - 10.1016/j.cell.2020.05.013

M3 - Article

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AN - SCOPUS:85086585557

SN - 0092-8674

VL - 181

SP - 1547-1565.e15

JO - Cell

JF - Cell

IS - 7

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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