TNFα reduces inhibitory transmission in young Trem2 R47H Sporadic Alzheimer rats before observable Aβ and brain pathology

rats, which carry the Alzheimer’s disease (AD) risk factor p.R47H variant of the microglia gene and produce human Aβ. Previously, we demonstrated that supraphysiological TNF-α boost glutamatergic transmission and suppresses Long-term-Potentiation (LTP), a surrogate of learning and memory, in peri-adolescent rats (). Here we tested the effect of the p.R47H variant on GABA transmission. We report that GABAergic transmission is decreased in rats. This decrease is due to the acute and reversable action of TNF-α and is not associated whit changes in human Aβ levels and pathological brain lesions. Thus, the p.R47H 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, Aβ-independent pathway leading to dementia.