Pleiotropic cytokine IL-6 regulates various processes in the body including neuronal functions. IL-6 can signal through its membrane bound receptor IL-6R, which associates with IL-6 signal transducer gp130 IL-6st/gp130 (classical signaling), or binds to soluble IL-6R to act on any cell that that expresses IL-6st/gp130 (trans-signaling). Alzheimer’s disease related enzyme BACE1 has critically important roles in synaptic function and cleaves IL-6st/gp130 as well as IL-6R.Therefore, we hypothesize that BACE1 could be essential for the alteration of neuron excitability and synaptic plasticity via modulation of IL-6 signaling. To record discharge activity of neuronal networks in acute cerebellum slices, multielectrode arrays (MEA) were used and synaptic plasticity evaluated in acutely isolated hippocampus sections by inducing long term potentiation (LTP) in CA1 through Schaffer collaterals and assess modulatory effects on IL-6 on these processes with and without BACE1 inhibition. IL-6 caused a significant but reversible decrease in LTP. Combined with BACE1 inhibition by Verubecestat or AZD3839, the effect of IL-6 was faster however was not different in magnitude. Interestingly, these recordings revealed a dramatic rebound effect with BACE1 inhibitor AZD3839 during wash out phase of IL-6, which did not occur with Verubecestat. Furthermore, spontaneous neuronal activity in cerebellar slices notably decreased upon perfusion with IL-6 and recovered during wash out. Both BACE1 inhibitors prevented the inhibitory effects of IL-6. These results point out the importance of BACE1 for IL-6 signaling pathways affecting neuron firing whereas alterations of synaptic plasticity were mainly mediated by classical signaling not requiring receptor shedding by the enzyme.