Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts
Nicholas L. Weilinger,
Kai Yang,
Hyun B. Choi,
Christopher J. Groten,
Stefan Wendt,
Madhuvika Murugan,
Leigh E. Wicki-Stordeur,
Louis-Philippe Bernier,
Prashanth S. Velayudhan,
Jiaying Zheng,
Jeffrey M. LeDue,
Ravi L. Rungta,
John R. Tyson,
Terrance P. Snutch,
Long-Jun Wu,
Brian A. MacVicar
Affiliations
Nicholas L. Weilinger
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Corresponding author
Kai Yang
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Hyun B. Choi
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Christopher J. Groten
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Stefan Wendt
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Madhuvika Murugan
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Leigh E. Wicki-Stordeur
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Louis-Philippe Bernier
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Prashanth S. Velayudhan
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Jiaying Zheng
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Jeffrey M. LeDue
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Ravi L. Rungta
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
John R. Tyson
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
Terrance P. Snutch
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
Long-Jun Wu
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Brian A. MacVicar
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Corresponding author
Summary: 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.
