TNFα reduces inhibitory transmission in young Trem2R47H Sporadic Alzheimer rats before observable Aβ and brain pathology

Abstract

Trem2R47H rats, which carry the Alzheimers disease (AD) risk factor p.R47H variant of the microglia gene TREM2 and produce human A{beta}. Previously, we demonstrated that supraphysiological TNF- boost glutamatergic transmission and suppresses Long-term-Potentiation (LTP), a surrogate of learning and memory, in peri-adolescent Trem2R47H rats (Ren et al., 2020). Here we tested the effect of the p.R47H TREM2 variant on GABA transmission. We report that GABAergic transmission is decreased in Trem2R47H/R47H rats. This decrease is due to the acute and reversable action of TNF- and is not associated whit changes in human A{beta} levels and pathological brain lesions. Thus, the p.R47H TREM2 variant changes the excitatory/inhibitory balance between glutamate and GABA transmission, favoring excitation. This unbalance could potentiate glutamate excitotoxicity and, over time, contribute to neuronal dysfunction, enhanced neuronal cells death and neurodegeneration. Future studies will determine whether this unbalance represents an early, A{beta}-independent pathway leading to dementia.