Neurotrophic-mimetic strategy to rescue synaptic plasticity and cognitive functions in a mouse model of Down syndrome

Down syndrome (DS) is caused by the triplication of human chromosome 21, and it is the most frequent genetic cause of cognitive disabilities. Although numerous studies have shown that cognitive impairment possibly arises from dysfunction of the hippocampal circuit, there is little insight into neurobiological bases of these abnormalities, and thus, there has been little progress in defining effective treatments. The trisomic Ts65Dn mouse model of DS reproduces the essential cognitive disabilities of the human syndrome. Previous studies in this model have shown that impaired synaptic plasticity of mature hippocampal neurons and decreased hippocampal adult neurogenesis are main determinants in reducing cognitive functions in DS animal models. Currently, most preclinical therapeutic approaches in the DS mouse models have focused on rescuing either one or the other of these impairments. Interestingly, we have found that the expression of Brain-Derived Neurotrophic Factor (BDNF) is decreased in the brains of DS patients. On the other hand, BDNF signaling modulates both synaptic plasticity, and adult neurogenesis. Therefore, we propose to promote BDNF/TrkB signaling using a BDNF-mimetic drug with the twofold aim of rescuing synaptic plasticity and increase adult neurogenesis toward the rescue of cognitive functions in Ts65Dn mice. Our results indicate that indeed promoting BDNF/TrkB signaling rescued hippocampal synaptic plasticity, increased dentate adult neurogenesis and restored cognitive performances in different behavioral tasks in Ts65Dn mice. Overall, our experiments show in a reliable animal model of DS the efficacy of a novel and multifaceted therapeutic approach with good potential to be translated into clinical practice.


Presented at:
11th Forum of European NeuroScience (FENS), Berlin, Germany, July 7-11 2018
Year:
Jul 07 2018
Keywords:
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 Record created 2018-07-07, last modified 2018-09-13


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