Abstract
Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies.
Highlights
Many neurodegenerative diseases are associated with characteristic changes in the behavioral profile of affected individuals
Frontotemporal dementia (FTD) comprises a group of clinical syndromes unified by underlying frontotemporal lobar degeneration (FTLD) pathology, which leads to disorders of behavior, language and executive function (Woollacott and Rohrer, 2016)
In order to analyze the impact of forebrain specific, neuronal wild-type hTDP-43 expression in multiple behavioral domains, we used previously generated TAR DNAbinding protein 43 (TDP-43) Tg mice with a tet-off system and the CaMKIIα promoter that model aspects of human TDP-43 proteinopathies (Igaz et al, 2011)
Summary
Many neurodegenerative diseases are associated with characteristic changes in the behavioral profile of affected individuals. Several neurodegenerative diseases display TAR DNAbinding protein 43 (TDP-43) pathology and this protein was identified as the main component of the distinctive cytoplasmic aggregates seen in the vast majority of ALS cases and about half of the cases of FTD (FTLD-TDP; Neumann et al, 2006; Baralle et al, 2013). It is clearly not possible to faithfully model every clinicopathological feature of the FTD/ALS spectrum in rodents, transgenic (Tg) mice have been shown to recapitulate major aspects of human FTD and ALS These include animal models based on the genetic manipulation of Tau, TDP-43, SOD1 and C9ORF72, among others, each one displaying specific but partial features of these diseases (Roberson, 2012; Philips and Rothstein, 2015)
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