Treatment with β-2 adrenergic receptor agonists: a tool for improving brain developmental alterations in Down syndrome?

Down syndrome (DS), a genetic condition (incidence: 800/1000) caused by triplication of human chromosome 21, is characterized by Intellectual disability (ID) starting from infancy. ID is attributable to early reduction of neurogenesis accompanied by dendritic pathology. At present, there are no therapies for the treatment of cognitive defects in DS. In the present study, we used the Ts65Dn mouse model of DS in order to establish whether it is possible to pharmacologically improve the trisomy-linked defects. The screening of two libraries of FDA-approved drugs in neural progenitor cells from Ts65Dn mice revealed various hits with a pro-neurogenic effect. Among these hits, Clenbuterol (CL) and Salmeterol (SALM), two β2-adrenergic agonists used for the treatment of asthma, resulted particularly effective. Based on this evidence, we treated Ts65Dn mice from postnatal day 3 (P3) to P15 with different doses of CL or SALM (from 0.01 to 2.0 mg/kg/day), in order to establish whether the effects elicited in vitro are replicated in vivo. We focused on the hippocampal dentate gyrus, a region fundamental for declarative memory. We found that, at variance with the in vitro experiments, treatment with CL or SALM did not restore neurogenesis in Ts65Dn mice. Treatment, however, fully restored dendritic spine density and dendritic complexity of the hippocampal granule cells and the lowest tested dose was sufficient to elicit these effects. This study provides novel evidence that two β2-adrenergic agonists are able to restore dendritic development in a DS mouse model. Importantly, even the lowest dose was sufficient to elicit this effect. After a translation that takes into account species-specific metabolic differences, this dose is in the range of doses used in children for the treatment of asthma. Thus, our study suggests that treatment with CL or SALM may represent a suitable therapy to correct dendritic pathology in children with DS.