Impact of TREM2 on hippocampal network oscillations in Tg2576 mice modeling amyloid-β pathology.

Abstract

Loss of function mutations in gene encoding triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with the risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data for indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology in AD. However, mechanisms by which TREM2 contributes to increased predisposition to AD and influences its progression still remain ill-defined. We investigated the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal neuronal network oscillations in wild-type and Aβ overproducing Tg2576 mice by in vivo monitoring spontaneous and brainstem stimulation-induced local field potentials from CA1 region under urethane anesthesia. Functional impairment of TREM2, either in TREM2(Het) or TREM2(Hom), resulted in increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Furthermore, deficiency of TREM2 significantly reduced the power of stimulation-induced hippocampal theta oscillation in Tg2576 mice compared to wild-type mice. However, dysfunction of TREM2 did not influence hippocampal theta-phase gamma-amplitude coupling per se, given that both TREM2 intact and TREM2 total deficient Tg2576 mice had a comparable decrease in the phase-amplitude coupling between theta and gamma oscillations when compared to wild-type counterparts. Our findings indicate a TREM2-dependent microglial function in the hippocampal neuronal network oscillations in both physiological conditions and the setting of Aβ overproduction.