During early stages of Alzheimer’s disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional and behavioural deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence point to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. Here, we proposed a novel Aβ-mediated mechanism of loss-of-function of G-protein-coupled activated inwardly-rectifying potassium channel (GirK/Kir3), which controls neuronal excitability, to contribute to the alteration of hippocampal inhibitory neurotransmission, and subsequent network hyperactivity and hypersynchrony in AD. We have studied the relationship between GirK channel and the effects of Aβ 1) at the molecular level, on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, 2) at the synaptic level, on the septohippocampal fimbria-CA3 synapse, pivotal for the maintenance of hippocampal rhythms related to learning and memory processes and 3) at the behavioral level, on learning and memory capabilities in an in vivo non-transgenic model of AD. Our results indicate that Aβ modulates the gene expression of GirK channels in the hippocampus, and decreases GirK channel conductance in the septohippocampal neurotransmission. Finally, data collected from learning tasks (habituation to the open field and new object recognition) showed significant differences between controls and Aβ groups or animals injected with Tertiapin-Q (GirK blocker). Taken together, our results point out that GirK channels could contribute to the imbalance in excitatory/inhibitory neurotransmission in the hippocampus that causes aberrant network activity and early cognitive impairment in AD models and emerges as an interesting potential therapeutic target to be studied in AD preclinical stages.