Antibiotic treatment induces activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus

Abstract

Antibiotics are widely applied for the treatment of bacterial infections, but their long-term use may lead to gut flora dysbiosis and detrimental effects on brain physiology, behavior as well as cognitive performance. Still, a striking lack of knowledge exists concerning electrophysiological correlates of antibiotic-induced changes in gut microbiota and behavior. Here, we investigated changes in the synaptic transmission and plasticity together with behaviorally-relevant network activities from the hippocampus of antibiotic-treated mice. The prolonged antibiotic treatment led to a strong reduction of myeloid cell pools in bone marrow, circulation and those surveilling the brain. Upon antibiotic treatment, circulating Ly6Chi inflammatory monocytes adopted a proinflammatory phenotype with increased expression of CD40 and MHC II. In the central nervous system, microglia displayed typical signs of activation with elevated CD40 and MHC II expression, as well as increased IL-6 and TNF production. Concomitantly, we detected a substantial reduction in the synaptic transmission in the hippocampal CA1 after antibiotic treatment. In line, carbachol-induced cholinergic gamma oscillation were reduced upon antibiotic treatment while the incidence of hippocampal sharp waves was elevated. These changes were associated with the global changes in the expression of neurotrophin nerve growth factor and inducible nitric oxide synthase, both of which have been shown to influence cholinergic functions. Overall, our study demonstrates that antibiotic-induced changes in the gut microbiome and immune cell function are associated with a drastic reduction in the synaptic transmission and gamma oscillations in the hippocampus, a brain region that is critically involved in mediation of innate and cognitive behavior.