Ya’el Courtney, a senior cellular and molecular biology major at Kent State University, investigated the function of schizophrenia risk gene CSMD1.
Development and plasticity of neural circuits require targeted loss or “pruning” of excess synapses. The immune complement cascade is one molecular mechanism that tags synapses for pruning by microglia. The Broad Institute is a unique research institution where experts from various fields work together in a highly integrated manner. I was amazed by the caliber and concentration of science happening around me and the willingness of these world-class scientists to mentor a rising generation and help us grow. This was true of not only my mentor, but of everyone I reached out to during my time here. I have grown more quickly than I ever imagined in terms of my technical lab skills, my ability to communicate scientifically, and my confidence and excitement about pursuing my dream job: being a scientist.While we know the complement cascade is implicated in pruning, we do not fully understand its regulation in the brain or the possible downstream processes affected when healthy synaptic pruning does not occur. Aberrant pruning is thought to contribute to a variety of neurodevelopmental disorders including schizophrenia (SCZ). In seeking to understand the interplay between the immune system and the brain in development, this study interrogated a gene robustly implicated by SCZ genome wide association studies, encoding the proposed complement inhibitor CSMD1. Previous work from the Stevens lab has shown that CSMD1 inhibits complement deposition and increases pruning in the mouse visual system, but work has not characterized its effects in an area more pertinent to SCZ: the prefrontal cortex.
We utilized immunohistochemistry to characterize cortical cytoarchitecture, synapse density, and neural circuit development in the prefrontal cortex of CSMD1 knockout mice, which exhibit abnormal circuit function by electrophysiology. We found no gross abnormalities, signifying that the effects CSMD1 has on synaptic development are likely cell type and circuit specific. In the future, we will use electrophysiology to refine hypotheses towards particular cell types, circuits, and sub-regions. By investigating the role of CSMD1 in the prefrontal cortex, we move towards a more complete understanding of how the complement cascade mediates healthy development and how variants regulating CSMD1 may play a vital role in SCZ pathogenesis.
Project: Investigating the function of schizophrenia risk gene CSMD1
Mentors: Matthew Johnson, Stanley Center for Psychiatric Research