Partitioning the effects of schizophrenia risk variants on dynamics of the local synaptic translatome in cortex

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The search for much-needed new treatments for schizophrenia and related disorders has been hampered by complex underlying genetics and a poor understanding of the genetic effects on cell biology. This project will use novel methods for studying cell biology during brain development and exploit recent discoveries in DNA sequencing that have revealed a subset of genetic variants that substantially increase the risk of schizophrenia. This innovative approach will lead to a better understanding of the biology behind the genetic risks of schizophrenia, where in the brain they are relevant and when during the lifespan these genetic variants have the most impact. These methods will also enable the pinpointing of cell types most relevant for the targeting of novel therapies. A primary aim of my research will be to investigate the effects of high-risk genetic variants on the function of synapses. Synaptic proteins are synthesised from genetic material either within the cell body or locally at the synapses themselves. There is growing evidence, supported by my own research, that genetic variants contributing to the risk of schizophrenia exert greater impact on proteins synthesised at synapses. This project will focus on the synaptic synthesis of proteins in two models of gene variation associated with schizophrenia and compare their effects. These genes, abbreviated to TRIO and GRIN2A, are both known to contribute to the function of neuronal synapses, but it is not known whether alteration of these genes affects local protein synthesis, or how they influence vulnerability at the synapse. To be of most use to drug development, points of convergence among the biological effects of genetic variants need refining based on patterns of gene activity, which vary based on the age of the individual or the particular location in the brain. From previous work, we know that TRIO is active throughout life, peaking during early development, whilst GRIN2A is much less active before birth and becomes increasingly active from birth until adolescence. Therefore, alterations in these genes may have different effects at different stages of development and could ultimately contribute to the risk of schizophrenia at different times. I will investigate this by repeating analyses of synaptic protein synthesis in models of disrupted TRIO and GRIN2A function at different periods of brain development, each time comparing their effects. New technologies for sequencing gene activity in individual cells, available at the University of Exeter, will enable me to study where in the brain genetic variants influencing the risk of schizophrenia cause disruption and refine their effects on particular molecular systems. Together, this research takes forward new discoveries and technologies in the field of psychiatric genetics to condense the complex genetic architecture of schizophrenia into concentrated pockets of vulnerability. By defining when and where risk variants affect the activity of synaptic genes, we can facilitate much more targeted and effective treatment strategies for schizophrenia and related conditions.