Skip to main content

Genetics and physiology of adolescent development in telencephalic interneurons

Final Report Summary - ADOLESCENT DEV (Genetics and physiology of adolescent development in telencephalic interneurons)

Many psychiatric diseases, such as schizophrenia, depression and anxiety disorders, manifest during adolescence. Recent studies have implicated a key role of cortical inhibition in general and the fast-spiking (FS) subtype of inhibitory interneurons in particular in several aspects of schizophrenia. Understanding how diverse neuronal classes are wired and communicate to produce behavior is the basis for understanding neuropsychiatric disorders and can provide a framework for the rationale development of therapeutics.
We are carrying out a multidisciplinary approach using state of the art techniques entailing an open-ended screen to begin elucidating the genetics and connectomics behind adolescent maturation of the different cell types in the brain as well as a candidate approach to study the impact of transcription factor Sox6 -a key genetic regulator on a local neuronal network level in fast-spiking parvalbumin expressing basket cells.

We have since the start of the project established an independent research group by recruiting 4 postdocs and 3 PhD-students. We have in competition received additional funding to cover all costs for salaries (including my own), running costs, equipment as well as laboratory space until 2021. These funding sources includes a senior Swedish Research Council grant, StratNeuro, NIH, Karolinska Institutet salary grants for associate professor and PhD-students as well as a number of private foundations. I am integrated at the department as evident from my recent appointment as deputy director of graduate education. I have since the start of the project disseminated the results as an invited speaker at seven international conferences, have myself organized two international symposia and has been invited as external speaker at 10+ universities.

We have successfully performed the breeding strategies outlined in our proposal. Furthermore we have established FACS isolation and RNA-sequencing of EGFP+ interneurons (both batch and single cell sequencing) and used this to perform several studies that has been accepted for publication (including two in top-tier journal Science). These results have provided the scientific community with the first comprehensive map of complete transcriptome of all cell types in a part of the brain. These publications have already received nearly 300 citations in just two years and has been the starting point of world-wide efforts to fund initiatives to map the brain with regards to cell types as defined by gene-transcription. This work has thus had a profound impact on science policy making for several countries and holds promise to help shed light on some of our most complex diseases.

Furthermore, we have investigated the role of Sox6 in postnatal FS cell maturation using advanced mouse genetics for postnatal removal in combination with electrophysiological whole cell recordings to show that Sox6 is necessary for postnatal local connectivity changes in FS cells. We have in collaboration with Graziella DiCristo in Montreal to in detail describe the morphological axonal and presynaptic post natal changes in FS-cell output onto Pyramidal cells. (Manuscript in preparation). This collaboration had the additional benefit of allowing us to identify one of the molecular pathways downstream of Sox6.

Understanding the cellular make-up of the brain as well as key, functional and genetic, programs necessary for the maturation of cell types will have a profound impact on our understanding of late-onset psychiatric disorders and is likely to provide novel strategies for treating these disorders.