Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

被引:76
作者
Kazim, Syed F. [1 ,2 ,3 ,4 ,5 ]
Chuang, Shih-Chieh [1 ,2 ]
Zhao, Wangfa [1 ,2 ]
Wong, Robert K. S. [1 ,2 ]
Bianchi, Riccardo [1 ,2 ]
Iqbal, Khalid [3 ,4 ]
机构
[1] Suny Downstate Med Ctr, Robert F Furchgott Ctr Neural & Behav Sci, Brooklyn, NY 11203 USA
[2] Suny Downstate Med Ctr, Dept Physiol & Pharmacol, Brooklyn, NY 11203 USA
[3] Dept Neurochem, Staten Isl, NY USA
[4] SUNY Downstate, Ctr Dev Neurosci, NYSIBR, Staten Isl, NY USA
[5] Suny Downstate Med Ctr, Grad Program Neural & Behav Sci, Brooklyn, NY 11203 USA
来源
FRONTIERS IN AGING NEUROSCIENCE | 2017年 / 9卷
关键词
Alzheimer's disease; amyloid beta precursor protein (APP); amyloid beta (A beta); CA3; epilepsy; hippocampus; metabotropic glutamate receptor 5 (mGluR5); seizure; METABOTROPIC GLUTAMATE RECEPTORS; DISINHIBITED HIPPOCAMPAL SLICE; SYNCHRONIZED BURST DISCHARGE; AMYLOID PRECURSOR PROTEIN; MOUSE MODEL; A-BETA; COGNITIVE DEFICITS; EPILEPTIFORM DISCHARGES; IMPROVES COGNITION; PATTERN SEPARATION;
D O I
10.3389/fnagi.2017.00071
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer's disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at similar to 3 weeks of age [prior to amyloid beta (A beta) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human A beta precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/A beta antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABA(A) receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/A beta expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes A beta plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/A beta antibody and by mGluR5 blockade in 3xTg-AD mice.
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页数:17
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