PIs: Nicholas Katsanis, Ph.D. and Dimitrios Avramopoulos, MD, PhD
Large-scale population genetic studies have begun to map the genetic architecture of schizophrenia (SZ). We now know that the genetic contribution of this multifactorial trait arises from a variety of lesions that include a) rare copy number variants (CNVs) of strong effect; b) common non-coding alleles of mild effect; and c) rare coding alleles that cluster in biological modules. Our recent studies have afforded us the opportunity to synthesize genetic, genomic, and functional studies to dissect the contribution of microtubule and ciliary dysfunction to SZ and to develop physiologically relevant assays to interrogate the effect of genes and alleles as a means of augmenting statistical power. Here, we will continue to focus on a specific biological module, the protein cluster that regulates microtubule function as it relates to axon/dendritic growth and ciliary function, and to dissect its contribution to SZ in terms of CNV pathomechanism; regulatory mutations; and rare alleles of large effect. We are uniquely placed to measure the contribution of this module to SZ. First, we will improve our understanding of the 16p11.2 CNV pathology, one of the most significant contributors to SZ; drawing from expertise both from our group as well as from Projects 2, 3 and Core C, we will test the contributory hypothesis for KCTD13, a gene for which we and others have amassed strong, but indirect, genetic and functional evidence of involvement. Second, we will assay the downstream effect of changes in four microtubule genes, including changes of regulatory elements, on the rest of the transcriptome and on SZ associated genes and pathways (with Project 2 and Core B). Finally, we will implement our in vivo assays to interpret sequencing data on candidate SZ genes in order to establish the direction of effect of candidate pathogenic alleles and to measure the overall burden of these loci to SZ. Taken together, our work, upon intersection with the studies of the other Center components, will inform the genetic contribution and the biological mechanisms of microtubule (dys)function to discrete aspects of SZ pathology and potentially help improve the design of treatment paradigms and future clinical trials.
The main goal of the current proposal is to identify the molecular and neurobehavioral abnormalities in young adulthood resulting from the genetic mutations of the microtubule-related genes associated with schizophrenia (SZ), such as PCM1, DPYSL2, and 16p11 copy number variations (CNVs), and how these alterations can be exacerbated by adolescent social isolation to produce a full-blown psychiatric disorder in young adulthood. We hypothesize that mice with the microtubule-associated genetic mutations will display stress-related molecular alterations and abnormal prefrontal cortex (PFC) maturation during adolescence and/or young adulthood, leading to adult behavioral phenotypes resembling different dimensions of SZ. Aim 1 will identify the genetic mutations-produced neurobehavioral abnormalities that can be exacerbated by adolescent social isolation in mice. We will identify the effects of the genetic risk factors on SZ-related behaviors as well as maturation of GABAergic interneurons and dendritic spines of pyramidal neurons in the PFC. We will also examine if these phenotypes are exacerbated by adolescent social isolation. Aim 2 will determine the genetic mutationsproduced molecular changes that can be intensified by adolescent social isolation. Specifically, we will evaluate expression of the candidate stress-related factors and the global transcriptome changes in PFC. Aim 3 will identify alterations in stress-associated molecules in peripheral blood samples collected from two independent prospective cohorts and compare the human results with those from the mouse models. The project will determine alteration in stress-related molecular expression induced by genetic mutations, leading to impaired PFC maturation during adolescence and adult behavioral consequences, which may underlie susceptibility to detrimental effects of adolescent social isolation. Our project will facilitate future development of prognostic measures and biomarkers to help identify prodromal signs of the disease.