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

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 p75 NTR 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.3 Introduction:

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

“…Notably, we found a dendritic spine loss in all layers over time irrespective of the lesioned pathway, with more pronounced effects in the denervated layers. In this context, it is interesting to theorize that specific subpopulations of spines across layers are targets for homeostatic synaptic plasticity, e.g., through microglia-synapse interactions (Cramer et al, 2022).…”

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

“…Microglia, which are derived from the yolk sac, are the primary resident mononuclear macrophages in the retina and are regarded as the first line of active immune defenders. They express many pattern recognition receptors and immune receptors, such as AT1R, AT2R, and TβRII, empowering their function of guiding blood vessel formation, guaranteeing the survival of neurons, monitoring neuronal activity, pruning synapses of neurons, sustaining density of dendritic spines and clearing apoptotic cells or protein aggregates (Takahashi et al, 2005;Parkhurst et al, 2013;Cramer et al, 2022;He et al, 2022; Figure 1). Retinal microglia mainly present high branch structures to guarantee retinal homeostasis.…”