CA1 parvalbumin interneurons display alterations of myelin patterning driven by microgliosis in temporal lobe...

Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy, characterized by significant reorganization of hippocampal neuronal circuits. While changes in GABAergic inhibitory circuits are a major feature of this reorganization, other prominent alterations include hippocampal myelination disruption, neuronal loss, and pronounced glial and inflammatory responses. Recent studies have established that parvalbumin (PV +) interneurons in the hippocampus are partially myelinated under normal conditions, representing a notable structural feature of this interneuron subtype. However, whether interneuron myelination becomes altered in TLE has remained unexplored. Using a mouse TLE model, we investigated CA1 PV+ interneurons during epileptogenesis and chronic disease phases, examining numerical density and myelination patterns. We simultaneously tracked microglial responses and oligodendrocyte lineage cell populations (mature oligodendrocytes and their precursors). Our findings reveal that CA1 PV+ interneurons maintain their numerical density throughout disease progression but undergo marked myelination alterations. This dysmyelination occurs concurrently with pronounced microgliosis and changes in the dynamics of oligodendrocyte lineage cell populations, predominantly during epileptogenesis. Notably, pharmacological intervention with GW2580, a CSF1R inhibitor, administered for 8 days around the status epilepticus, prevented both PV+ interneuron myelination alterations and changes in oligodendrocyte lineage cell populations by blocking microglial proliferation. These results establish a link between microgliosis and alterations of myelin patterning in CA1 PV+ interneurons, advancing our understanding of interneuronopathy and TLE pathophysiology. The mechanisms identified share remarkable similarities with those observed in dysmyelinating and neurodegenerative diseases, including multiple sclerosis, suggesting potential common therapeutic targets.