2. Academic Validation
  3. Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts

Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts

  • Cell Rep. 2023 Sep 22;42(10):113128. doi: 10.1016/j.celrep.2023.113128.
Nicholas L Weilinger 1,  Kai Yang 2,  Hyun B Choi 2,  Christopher J Groten 2,  Stefan Wendt 2,  Madhuvika Murugan 3,  Leigh E Wicki-Stordeur 2,  Louis-Philippe Bernier 2,  Prashanth S Velayudhan 2,  Jiaying Zheng 3,  Jeffrey M LeDue 2,  Ravi L Rungta 4,  John R Tyson 5,  Terrance P Snutch 5,  Long-Jun Wu 3,  Brian A MacVicar 6
Affiliations

Affiliations

  • 1 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: nicholas.weilinger@ubc.ca.
  • 2 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • 3 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Stomatology and Department of Neuroscience, Université de Montréal, Montréal, QC, Canada.
  • 5 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • 6 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: bmacvicar@brain.ubc.ca.
PMID: 37742194 DOI: 10.1016/j.celrep.2023.113128
Abstract

Neuronal swelling during cytotoxic edema is triggered by Na+ and Cl- entry and is CA2+ independent. However, the causes of neuronal death during swelling are unknown. Here, we investigate the role of large-conductance Pannexin-1 (Panx1) channels in neuronal death during cytotoxic edema. Panx1 channel inhibitors reduce and delay neuronal death in swelling triggered by voltage-gated Na+ entry with veratridine. Neuronal swelling causes downstream production of Reactive Oxygen Species (ROS) that opens Panx1 channels. We confirm that ROS activates Panx1 currents with whole-cell electrophysiology and find scavenging ROS is neuroprotective. Panx1 opening and subsequent ATP release attract microglial processes to contact swelling neurons. Depleting microglia using the CSF1 receptor antagonist PLX3397 or blocking P2Y12 receptors exacerbates neuronal death, suggesting that the Panx1-ATP-dependent microglia contacts are neuroprotective. We conclude that cytotoxic edema triggers oxidative stress in neurons that opens Panx1 to trigger death but also initiates neuroprotective feedback mediated by microglia contacts.

Keywords

ATP release; CP: Molecular biology; CP: Neuroscience; P2Y12; ROS; cytotoxic edema; microglia; neuroprotection; pannexin-1; reactive oxygen species; swelling.

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