Neocortical functional network development at the microscale: impairments and mechanisms in Rett Syndrome.

The brain comprises intricate neuronal circuitry arranged in complex patterns. A key challenge in studying brain network topology is that microscopic networks at the microscale cannot be studied noninvasively in humans. It is particularly challenging to study microscale networks during early development in animal models as the brain is rapidly changing in size. This could have implications for deciphering how an individual can show apparently normal development before rapid decline. The neurodevelopmental disorder, Rett Syndrome, characterised by Mecp2 deficiency, is a pertinent example of this. In the present thesis, I aimed to thoroughly characterise early neocortical functional network development at the microscale and how this is disrupted in a Rett Syndrome mouse model, before examining some of the mechanisms involved. For translatability, I also tested the viability of using a graph theoretical approach in 3D, human tissue—cerebral organoids—for future research to study neocortical network development in health and disease. Micro-electrode array recordings of primary murine cortical cultures showed that Mecp2-deficient, Rett Syndrome model networks showed impairments in spontaneous spiking and bursting activity. They showed reduced global functional network connectivity and modularity. Simulations revealed deficits in computation of the balance of connection benefits/costs. Interestingly, Mecp2-deficient network deficits were seen as early as two weeks in vitro which precedes the putative onset of behavioural decline in this Rett Syndrome model (~8 weeks). Crucially, optogenetic suppression of parvalbumin-expressing inhibitory interneurons restored spatiotemporal spiking dynamics. Finally, human cerebral organoids did show complex topology and hub node features beyond that which could be explained by high firing rates at 180 days in vitro. To conclude, neocortical microscale functional networks mirror many aspects of macroscale network development, and several network features are disrupted in Rett ...