Imaging macroscopic cortical dynamics to understand sensorimotor dysfunction and recovery in a mouse model of Rett Syndrome

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Rett syndrome is a severe neurological disorder resulting from mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), a DNA binding protein that regulates brain development and function. The prevalence of Rett syndrome is estimated at 1 in 10,000 live female births where affected girls typically exhibit normal early postnatal development before experiencing a stagnation phase during the second year of life. The hallmark symptoms of Rett syndrome include loss of communication and motor skills, including purposive hand movements, breathing abnormalities and early onset seizures. Although most individuals with Rett syndrome live into adulthood their quality of life is severely impacted and they require 24-hour care. Progress in understanding the pathophysiology of Rett syndrome has been accelerated by the generation and availability of rodent models that recapitulate the developmental timeline and spectrum of patient phenotypes. Proof-of-concept pre-clinical studies demonstrate that re-introduction of the defective Mecp2 gene reverses some of the debilitating phenotypes associated with Rett syndrome giving hope to families that gene therapy could provide the 'golden bullet'. However, there are indications that re-expressing the missing MeCP2 protein recovers some body and brain functions, but not all, suggesting reversal may only be superficial. What is missing in our understanding of Rett syndrome is how loss of MeCP2 affects brainwide communication and behaviour and whether its reintroduction can drive high level brain function and phenotypic rescue. A major advance towards addressing this issue has been the recent development of optical methods which allow the simultaneous visualisation of neural activity across multiple brain regions in rodents using genetically encoded calcium sensors. We aim to use this method to establish how loss of MeCP2 affects inter-areal neural dynamics both at rest and while mice learn a novel touchscreen-based visuomotor reaching task. By imaging activity in wild type and MeCP2-mutant mice we will uncover the principal mechanism of brainwide communication breakdown that lead to deficits in high-level brain function and behaviour. Since female MeCP2-mutant mice show a mosaic expression of MeCP2 across the brain (i.e. ~40-80% of cells express MeCP2), we will use a second imaging approach that uses sheets of light to generate whole brain MeCP2 expression maps. This will allow us correlate changes in protein expression with disrupted brainwide neural dynamics and behavioural deficits. We will follow this up by asking whether reexpression of MeCP2 using viral-mediated reactivation can drive reorganisation of brainwide neural dynamics and recovery of high-level brain function and behaviour. To do this we will optimise methods for non-invasive gene reactivation in neurons across the brain and will employ optical imaging methods to map the extent of MeCP2 re-expression, reorganisation of neural activity and recovery of sensorimotor learning. Ultimately our research will provide new insights into how loss of MeCP2 leads to inter-areal communication breakdown during learning and the extent to which its reintroduction rescues high-level brain function and behaviour. This work has the potential to directly influence translational medicine through our ongoing links with the International Rett Syndrome Gene Therapy Consortium who strive to develop improved and effective treatments for Rett syndrome.