Synaptic dysfunction in progranulin-deficient mice

被引：122

作者：

Petkau, Terri L. ^{[1
,2
]}

Neal, Scott J. ^{[1
,2
]}

Milnerwood, Austen ^{[4
,5
]}

Mew, Ada ^{[1
,2
]}

Hill, Austin M. ^{[1
,2
]}

Orban, Paul ^{[1
,2
]}

Gregg, Jenny ^{[1
,2
]}

Lu, Ge ^{[1
,2
]}

Feldman, Howard H. ^{[3
,8
]}

Mackenzie, Ian R. A. ^{[6
,7
]}

Raymond, Lynn A. ^{[3
,4
,5
]}

Leavitt, Blair R. ^{[1
,2
,3
,5
]}

机构：

[1] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada

[2] Womens & Childrens Hosp, Vancouver, BC V5Z 4H4, Canada

[3] Univ British Columbia Hosp, Dept Med, Div Neurol, Vancouver, BC V6T 2B5, Canada

[4] Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 1Z3, Canada

[5] Univ British Columbia, Brain Res Ctr, Vancouver, BC V6T 1Z3, Canada

[6] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 4H4, Canada

[7] Vancouver Gen Hosp, Vancouver, BC, Canada

[8] Bristol Myers Squibb, Neurosci Global Clin Res, Wallingford, CT 06492 USA

来源：

NEUROBIOLOGY OF DISEASE | 2012年 / 45卷 / 02期

关键词：

Progranulin; Frontotemporal dementia; Synaptic dysfunction; Long-term potentiation; Neuronal morphology; Mouse model; GRANULIN-EPITHELIN PRECURSOR; FRONTOTEMPORAL DEMENTIA; KNOCKOUT MICE; GROWTH-FACTOR; PLASTICITY; MUTATIONS; NEUROPATHOLOGY; DISEASE; BRAIN; SEX;

D O I：

10.1016/j.nbd.2011.10.016

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Progranulin haploinsufficiency is a common cause of familial frontotemporal dementia (FTD), but the role of progranulin in the brain is poorly understood. To investigate the role of murine progranulin (Grn) in the CNS in vivo, we generated mice targeted at the progranulin locus (Grn) using a gene-trap vector. Constitutive progranulin knockout mice (GrnKO) show moderate abnormalities in anxiety-related behaviors, social interactions, motor coordination, and novel object recognition at 8 months of age, many of which differ between males and females. Analysis of synaptic transmission in 10-12 month old GrnKO male mice indicates altered synaptic connectivity and impaired synaptic plasticity. Additionally, apical dendrites in pyramidal cells in the CA1 region of the hippocampus in GrnKO males display an altered morphology and have significantly decreased spine density compared to wild-type (WT) mice. The observed changes in behavior, synaptic transmission, and neuronal morphology in GrnKO mice occur prior to neuropathological abnormalities, most of which are apparent at 18 but not at 8 months of age. We conclude that progranulin deficiency leads to reduced synaptic connectivity and impaired plasticity, which may contribute to FTD pathology in human patients. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：711 / 722

页数：12

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