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

Area of Science:

• Neuroscience
• Neuroinflammation
• Stroke Research

Background:

• Microglia modulate synaptic plasticity, but their role in pathological synapse elimination remains unclear.
• Understanding microglia-neuron signaling is crucial for developing stroke therapies.

Purpose of the Study:

• To elucidate the molecular mechanisms by which microglia contribute to synapse loss following ischemic stroke.
• To investigate the role of brain-derived neurotrophic factor (BDNF) in microglia-mediated synapse elimination.

Main Methods:

• In vitro organotypic hippocampal slice cultures and in vivo transient middle cerebral artery occlusion (MCAO) models.
• Genetic manipulation in mice including targeted deletion of microglial *Bdnf* and phospho-null mutations in gephyrin (Gphn).
• Analysis of synaptic changes, neuroinflammation, and phosphorylation states in vivo and in vitro.

Main Results:

• Microglia release BDNF 24 hours post-ischemia, downregulating glutamatergic and GABAergic synapses in the peri-infarct area.
• BDNF signaling via p75^NTR and TrkB receptors affects dendritic spines and gephyrin scaffold stability.
• Microglia activation and gephyrin phosphorylation (Ser268/270) occur in peri-infarct and contralateral hemispheres post-MCAO.
• Targeting microglial BDNF or Gphn phospho-null mutations reduced ischemic brain damage, neuroinflammation, and synapse loss.

Conclusions:

• Microglial BDNF plays a critical role in synapse elimination after ischemic stroke.
• Gephyrin phosphorylation is a key event in microglia-mediated synapse downregulation.
• Targeting the microglial BDNF-gephyrin pathway offers a potential therapeutic strategy for stroke recovery.