Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila  

作　　者：Liqun Fang Jingjing Duan Dongzhi Ran Zihao Fan Ying Yan Naya Huang Huaiyu Gu Yulan Zhu 

机构地区：[1]Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China [2]Department of Neurology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China [3]Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China

出　　处：《Neuroscience Bulletin》2012年第5期585-594,共10页神经科学通报（英文版）

基　　金：supported by grants from the Department of Health of Heilongjiang Province, China (2006-228);the Educational Commission of Heilongjiang Province, China(11531096);the National Natural Science Foundation of China (31100819, 30970980);the Natural Science Foundation of Guangdong Province, China (S2011040002239);the China Postdoctoral Science Foundation (2010-0480805)

摘　　要：Objective Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer＇s disease （AD）. Although amyloid-β （Aβ） aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons （PNs） in the olfactory lobe of the fruit fly. Methods Cholinergic spontaneous and miniature excitatory postsynaptic current （mEPSC） were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results In fly pupae （2 days before eclosion）, overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.Objective Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer＇s disease （AD）. Although amyloid-β （Aβ） aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons （PNs） in the olfactory lobe of the fruit fly. Methods Cholinergic spontaneous and miniature excitatory postsynaptic current （mEPSC） were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results In fly pupae （2 days before eclosion）, overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

关 键 词：Aβ peptide projection neurons Alzheimer’s disease NEUROTOXICITY electrophysiolgy cholinergic synaptic transmission 

分 类 号：Q423[生物学—神经生物学] TB53[生物学—生理学]