Biological principles of schizophrenia: adolescent cell type-specification and synaptic pruning in prefrontal cortex

PURPOSE AND AIMSSchizophrenia (SCZ) is a genetically complex and poorly managed disorder with a complicated pathology that generally manifests in early adulthood.

With few exceptions, animal model work has failed to match the knowledge produced by human genetics and clinical medicine.

We will unravel principles by which polygenic and rare variant risk for SCZ generates complex pathology via disrupting adolescent maturation of the prefrontal cortex.I hypothesize that adolescent brain maturation of prefrontal cortex circuitry is an important contributor to SCZ etiology and pathology.

Specifically, that genetic risk for SCZ converges on disruptions in late cell type specialization of Layer 2/3 neurons and that this specialization is related to afferent inputs to the PFC.To test these hypotheses, I propose the following aims:Determine if adolescent cell type specialization generalizes to human brain development.Investigate mechanisms behind adolescent cell type-specification in the prefrontal cortex, and whether this process relies on cell-intrinsic mechanisms or network activity.Explore if area-specific synaptic input to PFC is stable over time or if it is specifically targeted for synaptic pruning.It is my hope, with this application to build on the investments that my group has made over the last years to design a program where we avoid the temptation to identify the biology of single target genes but rather take a broader approach to investigate biological principles at play.