Oligomeric Amyloid-β-induced PIP2 Reduction Results In Disruption Of Excitatory Transmitter Release In Hippocampus

In Alzheimer ’s disease(AD),the abnormal release of neurotransmitter caused by amyloid-β(Aβ)oligomer is closely related to synaptic function defects.In the present study,we found that excessive activation of the metabolic glutamate receptor 5(mGluR5)reduced the level of phosphatidylinositol 4,5-bisphosphate(PIP2),resulting in a decrease in release probability.Inhibiting the activation of mGluR5 strongly prevented the decrease in PIP2 level induced by exogenous oligomeric Aβ42 and rescued Aβ42-induced suppression of release probability.We first showed that the axonal PIP2 level in cultured mouse hippocampal neurons was notably decreased by exogenous oligomeric Aβ42.Oligomeric Aβ42 suppressed the frequency of miniature excitatory postsynaptic currents(mEPSCs)in CA1 pyramidal neurons and the release probability at the synapse between the Schaffer collateral and CA1 pyramidal neurons without changing the number of active boutons.We then showed that Aβ42-induced PIP2 reduction was prevented by inhibition of phospholipase C(PLC).Blocking PLC activity also restored the decreased release probability induced by Aβ42.Lastly,we found that blocking mGluR5 rescued oligomeric AP42-induced reduction of PIP2 in axons and decrease in presynaptic release probability at the synapse between the Schaffer collateral and CA1 pyramidal neurons,whereas pharmacologically activating mGluR5 mimicked Aβ42-induced PIP2 and presynaptic defects,indicating that the mGluR5-PIP2 pathway plays a critical role in oligomeric Aβ-induced aberrant transmitter release.Therefore,inhibiting the activity of presynaptic mGluR5 can ameliorate Aβ-induced abnormal neurotransmitter release by inhibiting excessive hydrolysis of presynaptic PIP2 in AD,which may provide a new insight for early diagnosis and treatment of AD.