期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 46, 页码 15244-15259出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1918-14.2014
关键词
Behavioral phenotypes; frontotemporal dementia; neurodegeneration; proteinopathies; TDP-43; transgenic mice
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT-PRH 2009-0073, PICT 2011-1727]
- International Brain Research Organization (IBRO)
- Fundacion Florencio Fiorini, Fundacion Alberto Roemmers
- University of Buenos Aires (UBACyT)
- CONICET
- National Institutes of Health [AG032953, AG-17586]
- Koller Foundation for ALS Research
Transactive response DNA-binding protein 43 (TDP-43) mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically localized form of TDP-43 (TDP-43-Delta NLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive, and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test, and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-Delta NLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. To determine whether these symptoms were reversible, we suppressed Tg expression for 14 d in 1.5-month-old mice showing an established behavioral phenotype but modest neurodegeneration and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When Tg expression was suppressed in 6.5-month-old mice showing overt neurodegeneration, motor deficits were irreversible. These results indicate that TDP-43-Delta NLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies.
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