Organic Anion Transporter 1 Deficiency Accelerates Learning and Memory Impairment in tg2576 Mice by Damaging Dendritic Spine Morphology and Activity.
To investigate whether and how organic anion transporter 1 (OAT1) is involved in the process of Alzheimer's disease (AD), we crossbred OAT1 knockout mice with tg2576, the widely used AD model mice. Results here showed the heterozygous OAT1-deficient tg2576 mice developed a learning- and memory-related behavior deficiency and higher soluble Abeta amount in early stage (3 months old). Furthermore, the heterozygous mice brain slice also showed impaired long-term potentiation (LTP) and spontaneous excitatory postsynaptic currents (sEPSC). By crossbreeding heterozygous OAT1-deficient tg2576 mice with Thy-1 YFP mice, we got autofluoresced (layer 4/5 cortical neuron) heterozygous mice. By using two-photon microscope in the direct observation of mice brain in vivo or single photon confocal on slices, compared with control tg2576 mice, we found that the OAT1-deficient mice showed a higher spine numbers but with a much lesser maturity extent. Finally, by using glutamate uncaging method, we induced chemical LTP in brain slices and found that OAT1-deficient mice showed abnormal chemical-induced LTP, which meant that the deficient behavior may be caused by abnormal spine morphology and activity. Our results indicated OAT1 may be involved in AD process by regulating spine morphology and activity.
Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China, wuxinlin670522@gmail.com.
Xinlin
X
Wu
Jianqing
J
Zhang
Heng
H
Liu
Yansheng
Y
Mian
Birong
B
Liang
Hongbo
H
Xie
Shijun
S
Zhang
Baoguo
B
Sun
Houming
H
Zhou
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D006579:Heterozygote; D017774:Long-Term Potentiation; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000172:deficiency / Q000235:genetics*
D027362:Organic Anion Transport Protein 1; C105033:Slc22a6 protein, mouse