Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia

Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75(NTR)) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.

Automated summary

This study investigates the role of microglia in synapse elimination after ischemia and identifies brain-derived neurotrophic factor (BDNF) as a key player in this process. The researchers found that microglia release BDNF to downregulate glutamatergic and GABAergic synapses in the peri-infarct area. They also discovered that microglia activation and gephyrin phosphorylation are involved in neuroplasticity after middle cerebral artery occlusion (MCAO). Deletion of the Bdnf gene in microglia or GphnS268A/S270A mutation protects against brain damage, neuroinflammation, and synapse downregulation after MCAO.