Apr 24, 2020

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

BioRxiv : the Preprint Server for Biology
T. CramerShiva K Tyagarajan

Abstract

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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Mentioned in this Paper

Protein Methylation
Genome
Cross Reactions
Methylation
Cell Type
Analysis
Cell Array Analysis
Probes
Genome, Human
Array

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