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Genetics and physiology of adolescent development in telencephalic interneurons

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The connectomics of the adolescent brain

Many psychiatric diseases including schizophrenia and depression start during adolescence. Elucidating how networks of neurons develop and interconnect in the teenage brain could lead to new developments in therapy.

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Recent studies have pointed to cortical inhibition and, in particular, fast-spiking (FS) inhibitory interneurons in several aspects of schizophrenia. The part EU-funded ADOLESCENT DEV (Genetics and physiology of adolescent development in telencephalic interneurons) project has used this information to investigate the genetics and connectomics behind the immense changes seen during adolescent maturation. Using state of the art techniques, ADOLESCENT DEV achieved significant results for two major research arms – cell isolation and RNA profiling in the cortex and significantly, the impact of transcription factor, Sox6. A key genetic regulator on a local neuronal network level in FS parvalbumin expressing interneuron cells (basket cells), Sox6 controls differentiation of cortical interneurons. The team used fluorescence activated cell sorting and RNA sequencing of green fluorescent protein interneurons to produce a complete transcriptome of all cell types in the cortex. Research results have been accepted in several journals including two in the top-tier publication Science. Nearly 300 citations in two years from their published papers is a measure of the importance of the ADOLESCENT DEV results. The work has become the platform for mapping the brain in relation to cell types defined by their transcription products. This could eventually aid in elucidating some of the most complex diseases. Advanced mouse genetics with electrophysiological whole cell recordings in postnatal FS cells were used to investigate the role of Sox6 in postnatal FS cell maturation. Results showed that Sox6 is necessary for postnatal local connectivity changes in FS cells. In collaboration with another lab, they have also described the morphological axonal and presynaptic postnatal changes in FS cell output to pyramidal cells. These are the primary excitation neurons of the mammalian prefrontal cortex. Research results were presented at seven international conferences and more than ten universities. ADOLESCENT DEV itself has organised two international symposia. Neuronal circuitry development is a cornerstone of how the brain develops and becomes prey to disease. As such, the work has had a profound impact on science policy in several countries.

Keywords

Connectomics, disease, adolescence, ADOLESCENT DEV, Sox6

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