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Research Projects

Project 1

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.

Project 2

PIs: Mikhail Pletnikov, M.D., Ph.D.Atsushi  Kamiya, M.D., Ph.D., Robert H. Yolken, M.D., Ph.D.

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.

Project 3

PI: Akira Sawa, M.D, Ph.D.
 
Recent clinical studies that examine prodromal subjects and recent-onset schizophrenia (SZ) have indicated that stress-associated pathways are activated prior to and at the onset of the disease, in contrast to milder changes of the pathways in the chronic stages. In addition, human postmortem studies have demonstrated changes in dendritic spines of pyramidal neurons and parvalbumin (PV)-positive interneurons. These are key neural substrates for the excitatory-inhibitory (E-I) imbalance in prefrontal cortical (PFC) neuronal networks underlying cognitive deficits in SZ. Our preliminary data show changes in stress-associated molecules and interneurons in adolescence and young adulthood in mouse models that display altered adult behaviors relevant to SZ. These models carry genetic perturbations of microtubule-associated molecules and show mild deficits in early neurodevelopment. Based on this background, we propose the following two Aims: Aim 1 will determine and characterize the critical periods for changes in stress-associated cascades and E-I imbalance in several genetic mouse models with mild brain deficits in early development elicited by microtubule-associated genes; and Aim 2 will study the mechanisms of neurocircuitry-based behavioral changes associated with medial PFC (mPFC) and orbitofrontal cortex (OFC), such as working memory deficits and behavioral inflexibility. We will also investigate whether adolescent social isolation exacerbates the pathological signatures. Finally, we will intervene with the stress pathways in a molecule, cell type and brain region-specific manner during adolescence to try to rescue adult phenotypes (physiology, behavior). We believe the proposed study is innovative and will lead to the development of new tools for early diagnosis and intervention in cognitive deficits relevant to SZ and related mental disorders.
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