Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome

Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterizedby intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neuronspopulating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the densityof dendritic spines. No effective therapy currently exists for the improvement of brain development in in-dividuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drugscreening campaign showed that the β2-adrenergic receptor (β2-AR) agonists clenbuterol hydrochloride (CLEN)and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dnmodel of DS. The goal of the current study was to establish their efficacyinvivo, in the Ts65Dn model. We foundthat, at variance with theinvitroexperiments, treatment with CLEN or SALM did not restore neurogenesis in thehippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLENor SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells wererestored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALMare used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study sug-gests that treatment with these β2-AR agonists may be a therapy of choice in order to correct dendritic devel-opment in DS but is not suitable to rescue neurogenesis.