Addressing alterations of brain development in Down syndrome: insight into neurodevelopmental phenotypes in the Ts65Dn and Ts66Yah mouse models and effects of adolescent treatment with a BDNF mimetic in the Ts65Dn model

Down syndrome (DS) is a genetic condition caused by the triplication of human chromosome 21 (Hsa21), consistently associated with intellectual disability (ID). ID results from both impaired neurogenesis and dendritic pathology, characterized by dendritic hypotrophy and reduced spine density. Currently, there are no therapies for ID in DS. The Ts65Dn model, the most widely used model of DS, carries a triplication of approximately 90 Hsa21-homologous genes but also includes around 50 extra triplicated genes. To remove these additional genes, the Ts66Yah model was created using CRISPR/Cas9 technology. Like Ts65Dn mice, Ts66Yah mice exhibit deficits in hippocampus-dependent learning and memory, although their neuroanatomy remains largely unstudied. Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that promotes brain development by binding to the Tropomyosin-related kinase B (TrkB) receptor. Previous data showed that early postnatal treatment with 7,8-Dihydroxyflavone (7,8-DHF), a BDNF mimetic, rescued hippocampal development and memory in Ts65Dn mice. Based on this evidence, the thesis aimed to: - Assess early postnatal dendritic alterations in frontal cortex pyramidal neurons (P2 and P8) in Ts65Dn mice; - Investigate hippocampal dendritic development and neurogenesis in Ts66Yah mice at P15 and 3 months; - Establish whether adolescent treatment with 7,8-DHF (P25-P50/52) improves hippocampal development and memory in Ts65Dn mice. Results revealed that Ts65Dn pups showed mild dendritic hypotrophy at P2 and P8, consistent with delayed dendritic changes in newborns with DS. Unlike Ts65Dn mice, Ts66Yah mice exhibited normal neurogenesis and dendritic pattern at P15 and 3 months, indicating that this model is suitable for studying some, but not all, DS phenotypes. Adolescent treatment with 7,8-DHF in Ts65Dn mice restored dendritic maturation and enhanced memory through activation of the TrkB pathway. These findings suggest that adolescence is still a critical therapeutic window for ID in DS, highlighting the potential of 7,8-DHF for clinical trials in adolescents with DS.