Synaptic formation and pruning in the postnatal maturation of the cerebral cortex
PI: Akira Sawa, M.D., Ph.D.
Synaptic pathology, such as a decrease in the spine density, is a pathological hallmark of schizophrenia. This is likely associated with aberrant brain maturation in adolescence, which in turn underlies deficits in neurotransmission in schizophrenia. To elucidate molecular mechanisms for the synaptic pathology, we are studying the cascade involving Rho-like small G-proteins, especially Rac1 and its downstream mediator PAK1. We will examine regulatory mechanisms for Rac1/PAK1, especially those by DISC1 and Kalirin-7 (Kal-7) in conjunction with neural activity. To test how the Rac1/PAK1 cascade plays a crucial role in the pathology of schizophrenia, we will test for beneficial effects of PAK inhibitors in several animal models relevant to the synaptic pathology of schizophrenia. Promising compound(s) in the preclinical study will be considered for clinical trial in near future. Finally, we will also conduct genetic sequencing for these molecular targets to explore rare variants associated with schizophrenia and test their functional influences on molecular, histological, and behavioral phenotypes, possibly related to schizophrenia.
Centrosomal and cilial organization in the developing cerebral cortex
PI: Nicholas Katsanis, Ph.D.
Epidemiological studies have highlighted the strong influence of genetic susceptibility on the development of schizophrenia, which, in turn, raised the expectation that the identification of susceptibility loci will illuminate the causative cellular pathways. Despite substantial effort, success in this area has been relatively modest. Thus, we focus on representative copy number variants (CNVs), such as a 600kb CNV on 16p11.2, and genes coding for centrosomal proteins, many of which interact with the DISC1 protein complex (e.g., PCM1, BBS4). We will study newly generated PCM1 knockout mice in the context of the pathological trajectory of schizophrenia. Most importantly, we will also conduct genetic sequencing for these molecular targets to explore rare variants associated with schizophrenia and test their functional influences on molecular, histological, and behavioral phenotypes, possibly related to schizophrenia.
Axonal growth and environmental stressors in the developing cerebral cortex
PIs: David Valle, M.D., Dimitrios Avramopoulos, MD, PhD
Evidence from several sources, including genome-wide linkage and association scans, candidate gene association studies, and from our preliminary studies on the functional consequences of sequence variants, all implicate certain DPYSL2 variants as conferring risk for schizophrenia. Also, our preliminary data indicate that certain variants confer a sex-specific risk for schizophrenia and relate expression of DPYSL2 variants to mTOR signaling and environmental variables. Thus, these rare genetic variants suggest a mechanism for relating environmental factors such as perinatal stress to risk for schizophrenia. DPYSL2 encodes CRMP2, which plays key roles in the specification and growth of axons. CRMP2 is a member of the DISC1 interactome, binds microtubules, and functions as a cargo receptor to traffic certain essential proteins. Based on these platforms, we will conduct additional large scale sequencing studies to develop an exhaustive catalog of DPYSL2 variants, especially those associated with schizophrenia, and we will then determine the consequences of these perturbations in DPYSL2/CRMP2 function in association with environmental stressors.
Dendritic organization in the postnatal maturation of the cerebral cortex
Disturbances in dendritic organization are likely to underlie the pathology of schizophrenia. Here we focus on a molecular pathway involving DISC1, neuronal nitric oxide synthase (nNOS), and NudE-like 1 (NDEL1), all of which have been indicated as risk factors for schizophrenia. By utilizing various types of genetic interventions, including use of nNOS knockout mice, we will examine how this molecular pathway plays a role in dendritic organization in the postnatal maturation of the cerebral cortex. We will also conduct genetic sequencing for these molecules to explore rare variants associated with schizophrenia and test their functional influences on molecular, histological, and behavioral phenotypes, possibly related to schizophrenia.
Gene-environmental interactions for the postnatal maturation of the cerebral cortex with animal models
The pathogenesis of schizophrenia is likely to involve multiple interactions between genetic vulnerability and environmental factors. Among non-genetic factors, microbial infections are associated with increased incidence of mental diseases. We believe that experimental models based on identified genetic mutations and measurable environment factors can significantly advance our understanding of the mechanisms of gene-environment interactions (GEI) relevant to schizophrenia. We will evaluate the neurobehavioral effects and molecular biomarkers of GEI in mice with genetic modifications of DISC1 and its interactors exposed to either maternal immune activation or early postnatal chronic infection with Toxoplasma gondii.
Roles for immune molecules in the postnatal maturation of the cerebral cortex
PI: Robert H. Yolken, M.D., Ph.D.
Individuals with schizophrenia have increased humoral immunity to infectious and food antigens. Increased complement activation and increased levels of circulating immune complexes are found in individuals with this disease. The complement factor C1q that binds these complexes is also highly expressed at synaptic locations in the developing cortex. This project will test the mechanistic hypothesis of how early postnatal exposure to an environmental trigger, such as Toxoplasma gondii infection, will further exacerbate C1q activation in the brain of DISC1 mutant mice to contribute to GABA interneuron and spine density deficits in the developing frontal cortex.