| The presenilin1/2(PSENs)play an important role in regulating synaptic function and cognitive processes.Clinically,dementia patients often show abnormal function of frontal cortex in the early stage of disease.The medial prefrontal cortex(mPFC)is involved in the regulation of a variety of higher-order cognitive functions,including episodic memory.However,so far,the pathogenesis of PSENs in episodic memory has not been clear.Therefore,in the present study,using presenilin1/2 conditional double knockout mice(cDKO mice),we have investigated the effect of PSENs genes knockout on the mPFC related episodic memory and synaptic plasticity.Results are as follows:1.Effect of PSENs conditional double knockout on mPFC related cognitive functions in mice.1)cDKO mice exhibited the impaired mPFC-related episodic memory.2)cDKO mice exhibited the impaired basal synaptic transmission and synaptic plasticity in II/III-V pathway of mPFC.3)cDKO mice exhibited abnormal distribution of NMDAR and AMPAR,and showed the decreased expression of p-?Ca MKII-Thr286 and PSD-95 in synaptic level of mPFC.4)cDKO mice exhibited the impaired activity of?secretase in mPFC.5)cDKO mice exhibited the decreased amount of A?1-42 in cortex.2.Effects of A?1-42 monomer on mPFC-related cognitive functions and synaptic plasticity in cDKO mice.Studies have shown that physiological concentration of A?1-42 monomer plays an important role in cell survival,synaptic plasticity,and learning and memory.In addition,our studies have showed that the amount of A?1-42 was decreased in the cortex of cDKO mice.Thus,we hypothesized that the impaired episodic memory in cDKO mice might be caused by the decreased amount of A?1-42.Therefore,we have investigated the effects of exogenous A?1-42 monomer on the mPFC-related cognitive functions and synaptic plasticity in cDKO mice.1)Addition of exogenous A?1-42 monomer reversed the impaired synaptic transmission and synaptic plasticity at II/III-V pathway of mPFC in cDKO mice.2)Addition of exogenous A?1-42 monomer reversed the impaired mPFC-related episodic memory in cDKO mice.3)Addition of exogenous A?1-42 monomer reversed the reduced the synaptic expression of NMDAR,AMPAR,p-?Ca MKII-Thr286 and PSD-95 in cDKO mice.Thus,the above data have demonstrated that the impaired episodic memory of cDKO mice is due to the decreasment of A?1-42,which is caused by abnormal APP shearing.Studies have shown that A?1-42has a high affinity with?7 nicotinic acetylcholine receptor(?7-nAChR),and?7-nAChR plays an important role in neuroprotection,synaptic plasticity,and learning and memory.So,does the reduction of A?1-42in the mPFC of cDKO mice impair the cognitive functions by weakening the function of?7-nAChR?The results are as follows:4)cDKO mice exhibited the decreased?7-nAChR synaptic expression in mPFC.5)Addition of exogenous A?1-42 monomer reversed the decreased synaptic expression of ?7-nAChR in cDKO mice.6)Antagonistic?7-nAChR inhibited the reversal effect of A?1-42 monomer on the impaired mPFC-related episodic memory in cDKO mice.In conclusion,PSENs conditional double knockout results in the impairment of mPFC-related episodic memory,which is due to the reduced synaptic expression of NMDARs,AMPARs,p-?Ca MKII-Thr286 and PSD-95.In addition,addition of exogenous A?1-42monomer can improve the episodic memory,synaptic plasticity and expression of relevant proteins in cDKO mice via up-regulating?7-nAChR.Our study provides new experimental evidence for a comprehensive understanding of the role of PSENs genes in episodic memory,and is useful to understand the roles of A?1-42 in cognition and synaptic plasticity. |
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