Exploring the molecular and synaptic effects of genetic risk variants associated with schizophrenia

BACKGROUND:

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Worldwide, nearly 24 million people are currently diagnosed with schizophrenia, ranking it among the top 15 causes of disability. In comparison to the general population, individuals with this disorder experience a reduction in lifespan of approximately 28.5 years. Conventional antipsychotic drugs have a broad range of side effects, and approximately one-third of patients are classified as treatment-resistant, reflecting the poorly understood pathoaetiology of schizophrenia.

My research seeks to employ innovative methods for studying cell biology during brain development, building on recent discoveries in genetic studies that have identified a small group of 10 genes containing a genome-wide excess of highly penetrant coding mutations in patients with schizophrenia. One of these 10 genes is the Trio Rho Guanine Nucleotide Exchange Factor (TRIO) gene. In the brain, TRIO plays a crucial role in assisting neurons in forming connections and communicating with each other, which is vital for proper brain function.

Existing evidence suggests that genetic variants contributing to the risk of schizophrenia have a significant impact on proteins synthesised locally at the synapses. Therefore, my focus will be on the effects of high-risk genetic variants in the TRIO gene on synaptic function.

I aim to identify candidates for the prioritisation of novel therapeutics and prevention strategies by refining our understanding of where in the brain synaptically localized mRNAs are preferentially affected by rare highly penetrant risk variants in the context of age. Such results will have significant implications for the functional interpretation of psychiatric genetics data within the context of dynamic gene expression. Finally, the methods developed during this project could be applied to other animal models of psychiatric disorders to explore the effects of risk variants on the local synaptic translatome.

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METHODOLOGY:

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To explore where in the brain; or when genetic variants in TRIO influencing schizophrenia risk cause disruption and refine their effects on cell-type specific biological processes, I will take advantage of single-cell RNA sequencing, ribosome profiling, electrophysiological characterisation, and bioinformatics.

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RESULTS:

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I have started characterising the effects of Trio haploinsufficiency in rodent models using immunohistochemistry.

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During my first year of PhD, I also had a chance to attend the Neuroscience School of Advanced Studies: Functional Genomics and Neurogenetics in Venice, where I have met amazing professionals in clinical and research fields and explored various interdisciplinary approaches.

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FUTURE WORK:

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I will continue characterising Trio haploinsufficiency in rodent models using qPCR, Western Blot, multiplex fluorescent immunohistochemistry, and extracellular field potential recordings. To define changes in ribosome-associated transcripts at the developing synaptic translatome caused by the loss-of-function Trio variant, I will take samples from P0.5, P7, and P35 of postnatal brain development, isolate translationally active synaptoneurosomes, and extract ribosome-bound mRNA, which will be sequenced. Next, I will undertake differential expression analysis to contrast the effects of genotype and developmental stage on the local translatome to identify the potential age-specific effects of the Trio variant. Lastly, I will undertake single-cell transcriptional sequencing to determine cell-type-specific changes in the transcriptome.

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FUNDED BY:

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CONTACT: 

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kt533@exeter.ac.uk

Kamile Tamusauskaite

@tamusauskaite