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Translational NeuroscienceToward New Therapies$
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Karoly Nikolich and Steven E. Hyman

Print publication date: 2015

Print ISBN-13: 9780262029865

Published to MIT Press Scholarship Online: September 2016

DOI: 10.7551/mitpress/9780262029865.001.0001

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How Might We Get from Genes to Circuits to Disease?

How Might We Get from Genes to Circuits to Disease?

(p.117) 8 How Might We Get from Genes to Circuits to Disease?
Translational Neuroscience

Tobias Kaiser

Yuan Mei

Guoping Feng

The MIT Press

Recent advances in the identification of risk genes for psychiatric disorders have set the stage for functional interrogation of disease related-circuits and underlying mechanisms of pathophysiology. Still, investigators face significant challenges: hundreds of genes may contribute to pathogenesis of a given disorder (polygenicity and genetic heterogeneity); risk alleles may only cause the disease in combination with other factors (reduced penetrance); commonly used rodent models may have significant limitations in studying psychiatric disorders, due to differences in brain structure and function with humans. To address these challenges, high-throughput functional assays should be developed in combination with iPSC technology and novel genome-engineering technologies, as these will help identify common pathways and mechanisms onto which multiple risk genes may converge. To overcome limitations of current animal models, novel genome-editing technologies provide an opportunity to generate better models (e.g., the common marmoset) to dissect disease-relevant circuit dysfunction. Finally, powerful new tools (e.g., CLARITY, dense neural circuit reconstruction, optogenetics) may help identify and test the relationship between distinct circuit defects and abnormal behaviors observed in these animal models. Such approaches are needed to span the gap between emerging genetic information and the symptomatic description of neuropsychiatric disorders.

Keywords:   Strüngmann Forum Reports, translational neuroscience, pathophysiology, genome editing, animal models, high-throughput functional assays, induced pluripotent stem cells, optogenetics, high resolution connectomics

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