Memory formation and cognitive processes that rely on activity-dependent synaptic plasticity are affected by local protein synthesis in the dendrites and axons of neurons, which shape the connections between neurons – the synapses. Malfunctioning synapses and synaptic connections are a feature of a large number of brain disorders, including developmental and neurodegenerative diseases, called “synaptopathies”.
Our lab has long been interested in understanding how synaptic protein synthesis and the associated actin remodelling that reshapes synapses is regulated, with a particular focus on how this occurs in development. A number of neurodevelopmental disorders such as Autism Spectrum Disorders and intellectual disability are characterized as synaptopathies, and there is increasing evidence that these disorders also feature dysregulated protein synthesis. One example of this is the most frequent form of inherited intellectual disability, Fragile X syndrome (FXS). FXS is due to the absence or mutation of a single protein, Fragile X mental retardation protein (FMRP). FMRP is a RNA binding protein that is involved in multiple steps of neuronal messenger RNA metabolism such as transport, stability and local protein synthesis. Our work along with that of others, has shown that ASD, schizophrenia and Alzheimer’s Disease (AD) are linked to FMRP function. Our goal is to understand the regulation of synaptic protein synthesis and actin remodelling during brain development and develop possible pharmacological approaches to modulate aspects of Fragile X Syndrome, autism spectrum disorders and schizophrenia.
Brain wiring and intellectual disabilities
One focus in the lab is on how local protein synthesis mechanisms regulate brain wiring and behaviour, and what this can tell us about how intellectual disabilities arise. We utilize mouse and fly model systems to study brain circuitry, in particular modelling genetic forms of intellectual disability in mice and flies such as. Methods include in utero electroporation, electrophysiology, advanced imaging techniques such as diffusion tensor imaging, and genetic fly approaches.
Synapse function in health and disease
Another focus in the lab is in studying how protein synthesis and actin remodelling at the synapse underlie normal function, and what underlies their dysfunction in neurodevelopmental disorders. Work from our lab has shown that FMRP, through its cytoplasmic interactor CYFIP1, links local protein synthesis to actin remodelling of the cytoskeleton. We utilize neuronal culture, biochemistry and RNA metabolism methods to approach these questions. In addition, we are also investigating the role of a subset of non-coding RNAs involved in spine formation and consolidation that are affected in FXS, and the mechanisms through which the regulation of the mRNA targets occurs.
Behaviour and electrophysiology in models of intellectual disabilities
A recent focus in the lab has been on integrating our studies at the level of synapse and circuits with function readouts in the animal that can be related to the features of neurodevelopmental disorders. By studying the effect these synaptic alterations have on circuits, electrophysiology and behaviour, we hope to further the understanding of these disorders and also study potential pharmacological interventions. We use mouse and fly behavioural paradigms for learning and memory, and social behaviour and communication.