Microglial depletion abolishes ischemic preconditioning in white matter

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Ischemic preconditioning (IPC) enhances tissue tolerance to subsequent ischemia, but its mechanisms in white matter (WM) are understudied.
• Human cerebral WM constitutes 50% of volume and is significantly impacted by stroke, unlike rodent models primarily focused on gray matter (GM).
• Understanding WM IPC is crucial for developing effective stroke treatments targeting WM damage.

Purpose of the Study:

• To investigate the role of microglia in white matter (WM) ischemic preconditioning (IPC) using a novel mouse optic nerve (MON) model.
• To test the hypothesis that microglia are essential for IPC-induced neuroprotection in WM.

Main Methods:

• Developed a novel CNS WM IPC model using the mouse optic nerve (MON).
• Depleted microglia using the CSF1R inhibitor PLX5622.
• Assessed functional and structural axonal recovery after simulated stroke (oxygen-glucose deprivation) via compound action potentials (CAPs) and stereology.

Main Results:

• Microglia depletion completely abolished IPC-mediated protection of axonal recovery and integrity.
• Preconditioned MONs showed improved CAP recovery compared to non-preconditioned controls, but this effect was lost upon microglia depletion.
• IPC protective effects on oligodendrocyte survival were also abolished by microglia depletion.

Conclusions:

• Preconditioned microglia are critical for mediating neuroprotection in white matter ischemic preconditioning (IPC).
• The identified 'preconditioned microglia' phenotype presents a potential neurotherapeutic target for CNS pathologies involving white matter damage.
• IPC-mediated protection in WM is intrinsic to the tissue and independent of retinal injury.