Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

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.

Disease-modifying effects of metabolic perturbations in ALS/FTLD

“…The presence of ubiquitinated and phosphorylated cytoplasmic inclusions of TDP-43 in the CNS of patients with ALS and FTLD [ 119 ], and the subsequent identification of TARDBP mutations in the sporadic and familial forms of these diseases [ 57 , 79 , 160 , 175 , 192 ], have led to the rapid development of TDP-43 transgenic models. Mutant Tardbp mice manifest some key features of human ALS and FTLD, including motor neuron loss, gliosis, motor and cognitive deficits, and early mortality [ 4 , 5 , 8 , 18 , 73 , 162 , 186 , 188 , 194 ].…”

From Mouse Models to Human Disease: An Approach for Amyotrophic Lateral Sclerosis

“…They found that embryogenesis was impaired in homozygous knockout mice, suggesting that TDP43 played a part in disease pathogenesis (106). Conversely, there was evidence that TDP43 synthesis was autoregulated, as heterozygous knockout mice did not have symptoms of neuromuscular disease and had normal protein expression (106)(107)(108). Symptoms typical of ALS were not exhibited in any of the generated knockout models.…”

“…Furthermore, in order to study the nature of GOF toxicity in ALS and the nature of GOF toxicity in ALS in which high levels of TARDBP mRNA and protein in defected neurons have been reported, researchers generated transgenic mice overexpressing human wild-type TDP43 carried by exogenous promoters such as Cre, Thy1.2, Prp and Camkllα (108,110). The mice in this model exhibited phenotypes similar to those observed in Camkllα mice.…”

Suppression of Conditional TDP-43 Transgene Expression Differentially Affects Early Cognitive and Social Phenotypes in TDP-43 Mice

“…Using a mouse model of TDP-43 proteinopathies that conditionally overexpresses the wild-type human TDP-43 protein (hTDP-43-WT) in forebrain neurons and reproduces neuropathological changes of the FTD/ALS spectrum (Igaz et al., 2011), we have recently shown that they display early behavioral phenotypes in the cognitive and social domains (Alfieri et al., 2016). Interestingly, these animals also exhibit progressive motor abnormalities after prolonged transgene expression (Alfieri et al., 2016). These behavioral features provide an interesting correlate to human disease, starting with a more “pure” FTD-like phenotype and later evolving into a FTD with motor neuron disease presentation (expressing some ALS-like features).…”

“…In this work, we aimed to investigate how short-term transgene suppression affects the early behavioral phenotypes displayed by conditional TDP-43-WT mice (Alfieri et al., 2016). In particular, we studied (1) if the cognitive and social phenotypes previously described were present after a shorter period (0.5 month) of transgene expression, and (2) the effect of the suppression on both affected domains and in motor behaviors, which were preserved after 1 month of transgene expression.…”