Atsushi Kamiya, Ph.D. - US grants

DESCRIPTION (provided by applicant): Disturbances in neuronal circuit formation may underlie the pathology of schizophrenia. This notion is supported by the fact that many genetic risk factors for schizophrenia have roles in neurodevelopment. Some of them likely act in common molecular pathways, displaying synergistic effects on key phenotypes in neurodevelopment, such as dendritic development, in which abnormalities have been reported in schizophrenia. Furthermore, the interaction between genetic and environmental factors, such as viral infection, may play a role in the disease etiology. One example is the case of Disrupted-in-Schizophrenia-1 (DISC1), which plays a role in various cellular processes in the developing cerebral cortex by mediating interaction with other genetic risk factors, such as nuclear distribution element-like (NDEL1). To produce animal models in which the expression of multiple risk genes can be manipulated simultaneously, in utero gene transfer is a useful method. The feasibility of this technique for examining the effect of genetic insults on neuronal circuits and brain functions was confirmed by our preliminary data, which showed that knockdown of DISC1 in the developing prefrontal cortex (PFC) leads to the impairment of mesocortical dopaminergic maturation and cognition. Nonetheless, it is unclear which DISC1-mediated cell behaviors in the specific developmental period lead to these phenotypes. Thus, in this study, to examine the role of the DISC1 pathway in specific developmental periods, we will utilize in utero Cre/loxP-mediated inducible gene transfer system. We hypothesize that (1) inducible knockdown of DISC1 in post-migratory neurons (inducible DISC1 KD) in PFC may segregate a role for DISC1 in dendritogenesis, independent from the secondary effects of DISC1 in dendrites caused by disturbed cell proliferation and/or migration, which may be required for mesocortical dopamine maturation and proper cognitive functions, (2) DISC1-NDEL1 interaction may be necessary for dendritic development, as well as the establishment of dopamine circuit and cognition, and (3) virus infection in post-migratory stages may exacerbate the phenotypes displayed in inducible DISC1 KD mice. To address these hypotheses, first, we will examine the role of DISC1 on dendritic development, mesocortical dopamine maturation, and cognitive functions in mice in which DISC1 is selectively suppressed in post-migratory stages in PFC by in utero inducible RNAi transfer. Second, we will examine synergistic effects of DISC1 and NDEL1 on these phenotypes in which concomitant suppression of DISC1 and NDEL1 occurs in post-migratory stages. We will also examine DISC1-NDEL1 interaction by "rescue" experiments with overexpression of DISC1 lacking the NDEL1 binding domain. Finally, in order to test the combined effect of immune activation and inducible knockdown of DISC1, we will examine the effect of the injection of PolyI:C at post-migratory stages in inducible DISC1 KD mice. This study will be able to contribute to the identification of a genetic risk-mediated molecular pathway in the specific developmental periods which may lead to disease susceptibility. PUBLIC HEALTH RELEVANCE: The interaction between genetic risks and environmental factors, such as viral infection, during brain development, may play a role in the etiology of schizophrenia. In this study, we will explore a role for DISC1, a major genetic risk factor for schizophrenia, in the specific cellular process in brain development, which may be crucial for the establishment of dopamine maturation and cognitive functions. We will also examine combined effects of genetic disturbance of DISC1 and immune activation. This study will be able to contribute to the identification of genetic risk-mediated molecular pathway in the specific developmental periods which leads to disease susceptibility.

DESCRIPTION (provided by applicant): Depression is the most prevalent stress-associated mental condition, imposing a serious economic burden on our society. Although there are a number of clinically effective treatments for depression and associated psychiatric conditions, a large segment of patients exhibit treatment-resistance to first-line interventions; limitations in current antidepressants call for novel interventions based on pathological mechanisms of depression. Accumulating evidence suggests that alterations in immune and inflammation processes, including changes in expression of pro- and anti-inflammatory cytokines are observed in patients with depression, whereby high stress environments may exacerbate their perturbed regulation. Consistently, chronic exposure to social defeat stress in rodents induces intracerebral activation of immune and inflammation systems, including elevation of certain cytokines, that are largely regulated by immune cells, including microglia which may underlie depressive animal behaviors. Notably, many natural products used in traditional Eastern medicine, such as Kanpo (adaptation of traditional Chinese medicine, Japan), have been shown to function as anti-inflammatory factors and antidepressants and have been empirically used for treatment and prevention of inflammation-associated human disease, including depression. Nonetheless, there is almost no mechanism-based evidence for the effectiveness of traditional herbal medicines in treatment of depression. Pachyman (1,3-¿-Glucans) is a main ingredient of several Eastern medicines, such as Yokukansan. In addition to the evidence of the antidepressant effect of Yokukansan, pachyman is reported to have anti-immune/inflammatory effects. Taken together, understanding the mechanistic link between its antidepressant and anti-inflammatory effects may open a new window for identification of novel preventive and/or treatment targets for depressive symptoms. In this project, we test the hypothesis that pachyman may ameliorate stress-associated immune/inflammation changes, leading to antidepressant effects. We will examine the protective and treatment effect of pachyman on stress-induced microglial immune changes and depressive behaviors using mice subjected to social defeat stress (Aims 1 and 2). Finally, based on our preliminary findings showing the strong suppressive effect of pachyman on stress-induced microglial IL18 expression in the prefrontal cortex, we will investigate whether microglia-specific knockdown of IL18 in the medial prefrontal cortex may ameliorate depressive behaviors induced by chronic social defeat stress. Defining the mechanism of action of pachyman may provide a basis for identifying novel drug targets for the prevention and treatment of depression and related mental conditions.

ABSTRACT The major goal of our NIDA-funded (R01DA041208) grant is to determine the molecular mechanisms of the interaction between genetic predisposition and adolescent cannabis exposure in producing long-term cognitive impairment in adulthood. The main focus of our study is the cell type-specific inflammatory pathways that mediate deleterious effects of adolescent treatment with ?9-tetrahydrocannabinol (?9-THC), a psychoactive cannabis constituent. We have recently reported that astrocyte-selective expression of a mutant form of disrupted in schizophrenia 1 (DISC1), a gene involved in neurodevelopment and synaptic plasticity, and adolescent ?9-THC treatment synergistically up-regulate inflammatory signaling in astrocytes, leading to impaired recognition memory (Jouroukhin et al., Biological Psychiatry 2018). These results suggest that genetic risk factors expressed in astrocytes may play a key role in moderating adverse effects of adolescent ?9-THC exposure. However, recent studies demonstrate that a chronic low dose of ?9-THC was able to reverse age-related cognitive decline and prevent neurodegenerative processes via protection from inflammation-induced cognitive damage in animal models of Alzheimer's disease. Considering these biphasic age-dependent effects of ?9-THC on cognition, we propose to extend our NIDA-funded studies to test the hypothesis that the opposite cognitive effects of ?9-THC in adolescent vs. aged mice could be explained by age-dependent changes in cannabinoid receptor 1 (CNR1)-mediated molecular cascades in astrocytes. To test this hypothesis, we will determine the role of astrocyte CNR1 in age-dependent (i.e., opposite) effects of ?9- THC on cognition by selectively deleting expression of CNR1 in astrocytes of adolescent and aged mice. This aim will establish the impact of aging on CNR1 signaling in astrocytes and its contribution to the ?beneficial? effects of low doses of ?9-THC on cognition in aged mice as compared to adolescent mice. We will also identify astrocyte-specific transcriptome signatures to underpin age-dependent effects of ?9-THC using cell type specific RNA-sequencing approach. This aim will determine the age-dependent and cell type-specific molecular mechanisms that underlie the ?beneficial? effects of low doses of ?9-THC on cognition in aged mice as compared to adolescent mice. The supplemental proposal will provide critical information for understanding the molecular mechanisms underlying adverse and beneficial age-dependent effects of ?9-THC on cognitive function, and will stimulate discovery treatment approaches for cognitive dysfunction in normal or pathological aging.