Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a pivotal role in various physiological and pathological processes, with involvement in innate immunity, inflammation, and tissue homeostasis. In the brain, IL-6 modulates neuroinflammatory responses, synaptic plasticity, and neuronal survival, thereby influencing processes such as neuroprotection, memory consolidation, and cognitive performance, while dysregulation of IL-6 signaling is associated with disorders such as cognitive dysfunction, major depression, neurodegenerative diseases and schizophrenia [26]. While in only a few cell types IL-6 acts via classical signaling by binding to membrane-bound IL-6 receptor (mIL-6R) to heteromerize with membrane-bound IL-6 signal transducer (IL-6st) glycoprotein 130 (gp130) [30,47], the vast majority of cells respond to IL-6 through trans-signaling, a process in which IL-6 binds to soluble IL-6R (sIL-6R) and subsequently associates with a dimer of gp130 [[37], [38], [39]]. In contrast to IL-6, cytokines leukemia inhibitory factor (LIF) binds to the membrane-bound receptor (mLIFR), which heteromerizes with gp130 and thereby acts as signal transducer [14,45]. LIFR is expressed in both cerebellum and hippocampus [28,55], however as LIF does not utilize a soluble binding receptor this cytokine is not able to act via trans-signaling [39].

The transmembrane protease ß-secretase or BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) can shed both mIL-6R and gp130 from cell membranes [19,29,57]. In the brain, the highest BACE1 expression is observed in the hippocampus and cerebellum [22]. BACE1 is highly expressed in neurons, predominantly localizing to synapses, indicative of a role in synaptic function [23] and BACE1 deficiency impairs synaptic vesicle release [6]. In the hippocampus, genetic or pharmacological inhibition of BACE1 causes impairment of synaptic plasticity by reducing long-term potentiation (LTP) in both mossy fiber and Schaffer collateral pathway synapses [6,17,18,52]. BACE1 is the rate-limiting enzyme in the amyloidogenic processing of amyloid precursor protein (APP) that results in the production of aggregation-prone amyloid-β monomers in Alzheimer's disease (AD) [43,49]. Therefore, BACE1 inhibitors were explored as a putative therapeutic strategy in AD clinical trials. However, inhibition of BACE1 worsened cognitive performance (for reviews see: [7,27,33,54]). This cognitive decline may be attributed to the increasing number of BACE1 substrates being identified [8,19,24]. Several BACE1 substrates, such as cell adhesion molecules L1, CHL1, and Neuregulin 1, are critically involved in regulating neuronal function, axonal guidance, plasticity, and myelination [13,58]. However, the mechanism linking BACE1 to IL-6 signaling in the brain with regards to spontaneous activity and synaptic plasticity is currently unknown. LIFR and gp130 exhibit extensive sequence homology in transmembrane and cytoplasmic regions and activate similar signaling pathways [14,32]. So far, LIFR has not been identified as a BACE1 substrate [19]. Here, we aimed to elucidate the effect of BACE1 on IL-6 and LIF induced modulation of spontaneous activity in cerebellum as well as long-term potentiation (LTP) in well-established Schaffer collateral pathway in hippocampus.