The discovery of CRISPR-Cas systems and their application to specifically edit genes provides us with new opportunities to treat neuropathologies at the genome level. To establish an effective approach of CRISPR-based gene editing in mammalian brain, we collaborate with the researchers identifying new Cas proteins, select appropriate viral and non-viral vectors for the delivery of CRISPR-Cas into the central nervous system, and trial their efficacy in vitro, ex vivo and in vivo. To thoroughly assess the outcomes of selective gene editing in brain cells, we use a range of animal and human models with the aim of applying them to treat nervous system disorders. Using these new tools, we strive to define the molecular signalling pathways that drive highly specific pruning of unnecessary synapses and projections in the developing brain. For this, we use both ex vivo tissue cultures and genetically modified mouse lines. We supplement animal models with the secondary use of surgically resected human brain tissue that allows us to directly investigate normal and aberrant human brain circuitry. We are developing novel molecular tools for rapid, selective and sensitive labelling of synaptic surface molecules and supplementing high-resolution fluorescent microscopy with electrophysiology techniques and animal behaviour experiments. We aim to define the synapses destined for elimination and to elucidate their molecular signatures, giving direct insight into the molecular cascades that are required for the developmental synaptic pruning in the maturing circuits of the mammalian brain.
