Developmental origins of mental illness: evolution and reversibility

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Overall abstract Most mental illnesses emerge during vulnerable windows of brain development to impact cognitive function in humans. While hundreds of genes and/or environmental factors have been linked to mental illnesses, even neighboring point mutations on a single gene (eg. Shank3) can lead to `early' disorders such as autism or `late' schizophrenia. This poses a double challenge to understanding their etiology and potential treatment – how to track the trajectory of circuit derailment and the relevance of such studies in animals like mice whose cognitive skills may be less well-characterized. Our proposed Conte Center renewal will tackle these problems directly by uniting four pioneering neurobiologists focused on the formation and refinement of neuronal circuits in two stages of development, fetal and pre-adolescent critical periods. Our central hypothesis is that whatever the predisposing environmental factors or genetic bases, the proximate cause of aberrant behavior in cognitive disorders will be found in distinct patterns of altered neuronal connectivity. First, to examine how excitatory- inhibitory balance is established in fetal life, Arlotta combines cutting edge stem cell, genomic, imaging and physiological recording technology for the longitudinal study of human brain organoids carrying specific gene mutation. Second, key conceptual insights from Hensch in the first phase of our Center identified the pivotal role of parvalbumin (PV+) cells in determining postnatal critical period timing. Because of their high metabolic activity, PV+ cells are vulnerable to oxidative stress in mental illness, as are the gamma oscillations which they generate (in association with cognition). Manipulations altering PV+ cell maturational profiles powerfully shift plastic windows in sensory cortex, indicating that malleability of critical periods themselves may contribute to cognitive disorders as well. Third, Hensch and Feng confirmed an impairment of multisensory integration in the insular cortex of mice carrying autism risk mutations in Shank3 and Mecp2. Notably, these lie on opposite ends of PV+ circuit hypo- or hyper-maturation. Here, we will take advantage of reversible and conditional genetic mutations in these genes to map critical periods for other higher functions of relevance: attention, cognitive flexibility, and social preference– all established in the Hensch lab. Moreover, for direct comparison to his mice, Feng will produce marmosets carrying Cre recombinase in PV+ cells or Shank3 deletion using CRISPR technology. His unique infrastructure will enable manipulation and analysis of the same circuits in this primate with better evolved frontal cortex and behaviors. Fourth, we capitalize on a sophisticated platform for complete 3D electron microscopic circuit reconstruction established by Lichtman during the first phase of our Center to compare and contrast the emergence of `connectopathies' from human organoids to mice and marmosets. Ultimately, reducing the stigma of mental illness through state-of-the-art neuroscience to train the next generation and conveying this knowledge through our strong, active Outreach program is the primary mission of the Conte Center at Harvard.