Mechanism Of NMDA Receptor And Its Subunits In Alzheimer’s Disease

Objective:1)Through investigating the connections between N-methyl-D-aspartate receptors（NMDAR） and β-amyloid protein （Aβ）-mediated long term potentiation （LTP）inhibition, then by the further study about the effects on LTP of different subunits ofNMDA receptor’ selective antagonist interacted with Aβ, in order to find thedifferent effects of various NMDAR subunits in the inhibition of LTP by Aβ.2)Toexploit the regulating mechanism of α7nicotinic acetylcholine receptors in synaptictransmission and synaptic plasticity, and the role of α7nicotinic acetylcholinereceptors in Aβ-mediated the inhibition on LTP.Methods: In this study, we used the methods of electrophysiology in vitro. Transverse slices ofthe hippocampus were prepared from male Wistar rats （age3-5weeks）. The brains were rapidlyremoved after decapitation and placed in Artificial cerebro-spinal fluid （ACSF）. Recordedthe excitatory post-synaptic potential （EPSP） and LTP induced by high frequencystimulation （HFS） in hippocampal dentate gyrus region. To calculate the ratio of HFS after60minutes created the average amplitude by the EPSP and the initial slope of the EPSP by basisto stimulate in the30minutes, which to be the amplitude of LTP. The data were shown by themeans±S.E.M. and in order to statistical comparison, we analysted the data by two-tailed Student’s test and two-way ANOVA.Results:1)The NR2B receptor competitive antagonist Ro25-6891or Ifenprodil prevent LTP ina dose-dependent manner and the low does Ro25-6891or Ifenprodil can reverse the inhibition onLTP induced by Aβ_1-42.2)The antagonist of NR2A NVP-AAM077does not effect Aβ_1-42-mediated inhibition on LTP.3)The antagonist of NR2D PPDA can resist Aβ_1-42-mediatedinhibition on LTP at the concentration of500nM.4)α7nicotinic acetylcholine receptorsagonist compound A （cpdA） emerges a persistent enhancement of synapitic transmission at10μM and this effect is related to the concentration of cpdA; In the high does of cpdA can overturnthe A1-42-mediated inhibition of LTP, but the α7nicotinic acetylcholine receptor positive allostericmodulator PheTQS can promote the promotion of cpdA on synapitic transmission and prevent theA1-42-mediated inhibition on LTP.Conclusions:1)The antagonists of NMDA receptor subunits NR2B and NR2D inhibit synapticplasticity, but can improve the Aβ_1-42-mediated synaptic plasticity injury, and this effect is in a dose-dependent manner, The antagonist of NR2A NVP-AAM077does not effect Aβ_1-42-mediated synaptic plasticity injury, These suggest that NMDA receptor NR2B and NR2D subunitsmay be involved in the Aβ-mediated excitotoxicity by Ca²⁺abnormal influx, but not NR2A.2)α7nicotinic acetylcholine receptor activity can promote synaptic transmission, and reverse the Aβ-induced inhibition of LTP, prompting that its agonists may become our potential researchdirections in the treatment of AD.