Brain-invading monocytes promote seizure-associated cognitive deficits and neurodegeneration

Seizure-associated cognitive comorbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne C-C chemokine receptor type 2 positive (CCR2+) monocytes into the brain. We have demonstrated that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious pathologies induced by SE, including BBB damage, microgliosis, and neuronal damage, following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that brief antagonism of CCR2 after SE prevents the working memory deficit in the Y-maze and retention memory in the novel object recognition test, but does not attenuate anxiety-like behavior in the open field arena. Notably, CCR2 antagonism was neuroprotective in the cortex and the CA1 region of the hippocampus. Neuronal numbers in the CA1 hippocampus, but not the cortex, correlated with retention memory. Our results indicate that blood-borne monocytes are a viable therapeutic cellular target for preventing cognitive comorbidities and neurodegeneration associated with seizures.