C1q neutralization during epileptogenesis attenuates complement-mediated synaptic elimination and epileptiform...

Area of Science:

• Neuroscience
• Immunology
• Epilepsy Research

Background:

• Aberrant C1q-C3 complement signaling in microglia and astrocytes contributes to synaptic dysfunction and neuronal loss in epilepsy.
• C1q-mediated synaptic dysfunction disrupts neuronal circuitry and can lead to network hyperexcitability.

Purpose of the Study:

• To investigate the therapeutic potential of C1q inhibition in preventing synaptic loss and attenuating epileptiform activity.
• To determine if blocking C1q-driven pathways at critical times is effective in a mouse model of epilepsy.

Main Methods:

• Examined microglial C1q and astrocytic C3 expression in mouse hippocampus post-pilocarpine-induced status epilepticus (SE).
• Administered C1q-neutralizing antibody or control IgG at 7 days post-SE.
• Assessed glial reactivity, dendritic spine density, and epileptiform activity via immunostaining, Golgi staining, and EEG.

Main Results:

• C1q expression increased in the subacute phase, and astrocytic C3 expression increased and persisted chronically.
• C1q antibody treatment at 7 days post-SE reduced microglial synaptic phagocytosis and astrocytic C3 activation.
• Intervention preserved dendritic spine density and decreased interictal spike frequency in chronic EEG recordings.

Conclusions:

• C1q is an upstream mediator of complement-driven neuronal loss during epileptogenesis.
• C1q blockade interrupts microglial engulfment and astrocytic C3 upregulation, preserving synaptic integrity and reducing epileptiform activity.
• C1q inhibition shows therapeutic potential for mitigating neuroinflammation, improving synaptic integrity, and reducing seizures in epilepsy.