Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice

Germana Cocozza, Maria Amalia di Castro, Laura Carbonari, Alfonso Grimaldi, Fabrizio Antonangeli, Stefano Garofalo, Alessandra Porzia, Michele Madonna, Fabrizio Mainiero, Angela Santoni, Francesca Grassi, Heike Wulff, Giuseppina D'Alessandro, Cristina Limatola

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the “pro-inflammatory” phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the “pro-inflammatory” phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Calcium-Activated Potassium Channels
Microglia
Motor Neurons
Amyotrophic Lateral Sclerosis
Nerve Degeneration
Phenotype
Intermediate-Conductance Calcium-Activated Potassium Channels
Muscle Denervation
Neuromuscular Junction
Muscle Weakness
Cholinergic Receptors
Paralysis
Spinal Cord
Muscles
Survival

Keywords

  • ALS
  • KCa3.1 channels
  • Microglia
  • Motor neurons
  • Mouse model
  • Neurodegeneration
  • Neuromuscolare junction
  • SOD1G93A
  • Spinal cord

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Cocozza, G., di Castro, M. A., Carbonari, L., Grimaldi, A., Antonangeli, F., Garofalo, S., ... Limatola, C. (Accepted/In press). Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2018.07.002

Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice. / Cocozza, Germana; di Castro, Maria Amalia; Carbonari, Laura; Grimaldi, Alfonso; Antonangeli, Fabrizio; Garofalo, Stefano; Porzia, Alessandra; Madonna, Michele; Mainiero, Fabrizio; Santoni, Angela; Grassi, Francesca; Wulff, Heike; D'Alessandro, Giuseppina; Limatola, Cristina.

In: Brain, Behavior, and Immunity, 01.01.2018.

Research output: Contribution to journalArticle

Cocozza, G, di Castro, MA, Carbonari, L, Grimaldi, A, Antonangeli, F, Garofalo, S, Porzia, A, Madonna, M, Mainiero, F, Santoni, A, Grassi, F, Wulff, H, D'Alessandro, G & Limatola, C 2018, 'Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice', Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2018.07.002
Cocozza, Germana ; di Castro, Maria Amalia ; Carbonari, Laura ; Grimaldi, Alfonso ; Antonangeli, Fabrizio ; Garofalo, Stefano ; Porzia, Alessandra ; Madonna, Michele ; Mainiero, Fabrizio ; Santoni, Angela ; Grassi, Francesca ; Wulff, Heike ; D'Alessandro, Giuseppina ; Limatola, Cristina. / Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice. In: Brain, Behavior, and Immunity. 2018.
@article{4cf95018aa6e488d8071b31c88bf6b0b,
title = "Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice",
abstract = "Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the “pro-inflammatory” phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the “pro-inflammatory” phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.",
keywords = "ALS, KCa3.1 channels, Microglia, Motor neurons, Mouse model, Neurodegeneration, Neuromuscolare junction, SOD1G93A, Spinal cord",
author = "Germana Cocozza and {di Castro}, {Maria Amalia} and Laura Carbonari and Alfonso Grimaldi and Fabrizio Antonangeli and Stefano Garofalo and Alessandra Porzia and Michele Madonna and Fabrizio Mainiero and Angela Santoni and Francesca Grassi and Heike Wulff and Giuseppina D'Alessandro and Cristina Limatola",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.bbi.2018.07.002",
language = "English (US)",
journal = "Brain, Behavior, and Immunity",
issn = "0889-1591",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice

AU - Cocozza, Germana

AU - di Castro, Maria Amalia

AU - Carbonari, Laura

AU - Grimaldi, Alfonso

AU - Antonangeli, Fabrizio

AU - Garofalo, Stefano

AU - Porzia, Alessandra

AU - Madonna, Michele

AU - Mainiero, Fabrizio

AU - Santoni, Angela

AU - Grassi, Francesca

AU - Wulff, Heike

AU - D'Alessandro, Giuseppina

AU - Limatola, Cristina

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the “pro-inflammatory” phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the “pro-inflammatory” phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.

AB - Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the “pro-inflammatory” phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the “pro-inflammatory” phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.

KW - ALS

KW - KCa3.1 channels

KW - Microglia

KW - Motor neurons

KW - Mouse model

KW - Neurodegeneration

KW - Neuromuscolare junction

KW - SOD1G93A

KW - Spinal cord

UR - http://www.scopus.com/inward/record.url?scp=85049311459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049311459&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2018.07.002

DO - 10.1016/j.bbi.2018.07.002

M3 - Article

C2 - 29981425

AN - SCOPUS:85049311459

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

ER -