| Amyloid-β(Aβ)oligomer-induced aberrant neurotransmitter release has been proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease(AD).In the present study,we found that knocking out the membrane protein EFR3A,a key component in the phosphatidylinositol 4-kinase(PI4K)complex,in CA3 region of the hippocampus in mice strongly prevented exogenous oligomeric Aβ-induced suppression of the frequency of miniature excitatory postsynaptic currents(mEPSCs)recorded from CA1 pyramidal neurons.By contrast,overexpression of EFR3A aggravated oligomeric AP-induced impairment in mEPSC frequency.By estimating the release probability at the synapse between the Schaffer collateral(SC)and CA1 pyramidal neurons(PNs),we found that oligomeric Aβ-induced decrease of mEPSC frequency was mainly due to a reduction in the presynaptic release probability,whereas the readily releasable pool size did not change.In addition,we observed a reduction in presynaptic release probability in AD mice at a specific age.Remarkably,knocking out EFR3A in CA3 area of the hippocampus significantly rescued aberrant release probability at the SC-PN synapse in these mice.We further found that oligomeric AP could greatly activate the mGLUR5-Phospholipase C pathway,leading to an aberrant reduction of(PtdIns(4,5)P2 in the presynaptic terminal,which results in a reduction of the presynaptic release probability.Our work demonstrates that knocking out presynatic EFR3A prevented oligomeric Aβ-induced aberrant activation of the mGLUR5-PLC pathway,thus restoring the abnormal synaptic transmission caused by Aβ-induced low level of presynaptic Ptdlns(4,5)P2. |
