RT Journal Article
SR Electronic
T1 Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.22.055087
DO 10.1101/2020.04.22.055087
A1 Teresa Cramer
A1 Raminder Gill
A1 Zahra S Thirouin
A1 Markus Vaas
A1 Suchita Sampath
A1 Sara B. Noya
A1 Philip K.-Y. Chang
A1 Peiyou Wu
A1 Philip A Barker
A1 Rosa C. Paolicelli
A1 Jan Klohs
A1 Shiva K. Tyagarajan
A1 R. Anne McKinney
YR 2020
UL http://biorxiv.org/content/early/2020/04/24/2020.04.22.055087.abstract
AB Microglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo, we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synaptic transmission within the penumbra area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate dendritic spine and gephyrin scaffold stability through p75NTR and TrkB receptors respectively. Post-MCAO, we report that in the penumbra and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation post-MCAO. Collectively, we report a new unanticipated role for gephyrin phosphorylation in inflammation and microglia activation for neuroprotective plasticity after transient ischemia.Competing Interest StatementThe authors have declared no competing interest.