TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.

Febrile seizures (FS) are common convulsive episodes in childhood and an important etiological component in epilepsy. However, most currently available antiepileptic drugs cannot prevent epileptogenesis and may even exacerbate it. Triggering receptor expressed on myeloid cell 2 (TREM2)-mediated microglial phagocytosis of inhibitory synapses may play a pivotal role in epileptogenesis; however, the role of TREM2 in FS-induced epilepsy remains unclear. We established a Sprague-Dawley rat model of juvenile prolonged FS to analyze the associated molecular changes, epileptic susceptibility, and seizures. Our results confirmed that prolonged FS resulted in increased TREM2 levels, excessive phagocytosis by activated microglia targeting inhibitory synapses, and elevated epileptic susceptibility and seizures. Administration of a CD33 agonist (monosialoganglioside 1, GM1), a negative moderator of TREM2 that reduces its levels, attenuated microglial phagocytosis of inhibitory synapses and weakened susceptibility to epilepsy and seizures. The inhibitory effects of TREM2 knockdown were similar to those of CD33 activation. Blocking the outward-facing region of phosphatidylserine (PtdSer) to prevent TREM2 recognition resulted in increased TREM2 levels and deteriorated microglial activation. Finally, although vesicular GABA transporter (VGAT) levels were higher in the prolonged FS rats treated with annexin V, susceptibility to epilepsy and seizures were aggravated. This study revealed that reducing TREM2 levels may inhibit prolonged FS-induced epileptogenesis by alleviating the phagocytic function of activated microglia targeting inhibitory synapses, while preventing TREM2 from recognizing PtdSer has the opposite effect.