Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia

Teresa Cramer, Raminder Gill, Zahra S Thirouin, Markus Vaas, Suchita Sampath, Sara B. Noya, Philip K.-Y. Chang, Peiyou Wu, Philip A Barker, Rosa C. Paolicelli, Jan Klohs, Shiva K. Tyagarajan, R. Anne McKinney

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Received Date: 2nd April 20

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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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