Aim: Acid-sensing ion channels 1a (ASIC1a) are widely distributed in the mammalian nervous system and in particular brain areas including the hippocampus. ASIC1a is highly permeable to Ca2+ and its activation has a crucial importance in numerous physiological and pathological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a channels in the synaptic alterations induced by Aβ, we carried out electrophysiological experiments investigating the effects of a ASIC1a-blocking monoclonal antibody ASC06-IgG on hippocampal long-term potentiation (LTP) and long-term depression (LTD) using an in vitro model ofAlzheimer’s disease (AD). Methods: We performed whole cell patch clamp recordings of CA1 pyramidal neurons in acute slices obtained from C57BL6J mice. NMDA- receptor dependent forms of Long Term Depression (LTD) and Long Term Potentiation (LTP) were elicited by electrical protocol. Excitatory neurotransmission changes were evaluated recording Paired Pulse ratio (PPR), AMPA NMDA ratio and spontaneous Exciatory post synaptic currents (sEPSCs). The ex vivo model of AD was obtained applying Aβ (200 nM) on slices for 30 minutes before recording. Results: We observed that blocking ASIC1a with the selective inhibitor Psalmotoxin-1 or with the novel ASIC1a-blocking monoclonal antibody ASC06-IgG, the Aβ-mediated alterations of synaptic neurotransmission and plasticity were prevented. Overall, these data demonstrate for the first time that ASIC1a is involved in the synaptic plasticity modifications triggered by Aβ. Conclusion: These findings suggest a neuroprotective effect of ASC06-IgG and highlight ASIC1a as a potential pharmacological target to treat memory decline and cognitive impairments.