Targeting aberrant Cl- homeostasis and GABAergic transmission in Down syndrome to design innovative therapeutic approaches

Down Syndrome (DS) is the most frequent cause of intellectual disability in children and adults, but other symptoms such as increased anxiety and sleep disorders also impact on the quality of life of DS patients and their families. Based on previous findings from our lab on adult DS mice, a pilot clinical trial will start in the near future addressing amelioration of DS cognitive symptoms by the FDA-approved diuretic bumetanide repurposed for the treatment of adult individuals with DS. Here, we will address whether the same pharmacological treatment can also rescue anxiety and sleep in DS mice. Moreover, since DS is a neurodevelopmental disorder, we will address whether and how treatment with bumetanide to young DS mice can rescue their defective brain development and attenuate DS symptoms later in life. Finally, we will also test new chemical compounds to find drugs able to still rescue DS symptoms, but devoid of the diuretic effect. Thus, the ultimate goal of this project is to offer a larger scientific background on which design new clinical trials also addressing anxiety and sleep disorders, and highlight new therapeutic windows for earlier (and possibly more effective) pharmacological intervention with drugs devoid of inconvenient side effects. If successful, this project may lead to a better life quality of individuals with DS and their families