Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse

Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-beta (A beta) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of A beta on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABA(A) antagonists whereas the late IPSP was removed by GABA(B) antagonists. A beta perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. A beta action mechanism was localized at postsynaptic level and most likely linked to GABA(B)-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABA(B) receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all A beta effects previously described. Thus, our findings suggest that A beta altering GirK channels conductance in CA3 pyramidal neurons might have a key role in the septohippocampal activity dysfunction observed in AD.