Synaptic, Cellular and Neural Circuit Dysfunction in Down Syndrome (360G-Wellcome-217199_Z_19_Z)

Down syndrome (DS) is a common genetic disorder resulting from an extra copy of human chromosome 21 (Hsa21). This gene dosage disorder is characterised by cognitive deficits and early-onset neurodegeneration. It causes significant impact on the quality and longevity of life. Presently, there are no therapies. The key aim of our proposal is to establish the mechanisms by which trisomy 21 causes cognitive impairment in DS. By using a unique complement of segmental trisomy-containing mouse models and human DS induced pluripotent stem cell-derived neurons, together with cutting-edge genetics, biochemistry, imaging, electrophysiology, neural circuit tracing and systems neuroscience, we will identify the genes that cause neurological deficits in DS, define the cells that are affected, and discover the mechanisms that underlie dysfunctional neural communication. Identifying the responsible proteins and their roles in the brain will allow us to devise innovative pharmacological and gene-based therapeutic approaches to reverse the deleterious cognitive phenotypes. Our research strategy is based upon a significant bank of preliminary data. By using the diverse but complementary research skills within our collaborative group, we have the potential to deliver greater understanding of, and life-changing therapies for, people with DS.