シンポジウム

シンポジウム Inflammation and psychiatric disorders

3S7-1 Neuroinflammatory features of the cytokine-induced animal model for schizophrenia；implication of the regional specificity Nawa Hiroyuki¹，Tsukano Hiroaki²，Shibuki Katsuei²，Kakita Akiyoshi³，Sotoyama Hidekazu¹，Namba Hisaaki¹ ¹Department of Molecular Neurobiology, Brain Research Institute, Niigata University，²Department of Neurophysiology, Brain Research Institute, Niigata University，³Department of Pathology, Brain Research Institute, Niigata University Cytokine-mediated mild chronic inflammation is implicated in the pathogenesis of schizophrenia. Many genetic studies of GWAS identified the major histocompatibility locus as a major risk component for schizophrenia and suggest the contribution of immune inflammatory processes to this illness. However, the etiological and neuropathological mechanisms underlying verbal hallucination and its age-dependent onset of schizophrenia remain to be clarified. To test the immune inflammatory hypothesis for schizophrenia, we administered a variety of cytokines to rodent pups, juveniles and adults and characterized neurobiological, pathological and behavioral consequences. In the neonatal stage but not the juvenile and adult stages, subcutaneously-injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral impairments associated with schizophrenia endophenotypes. Neonatally-EGF-treated animals exhibited persistent hyperdopaminergic abnormalities mainly in the nigro-pallido-striatal system. Once mal-development of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at post-pubertal stages. The EGF-treated model rats also exhibited mild gliosis and white matter shrinkage without apparent neuronal loss during aging. Among several neocortical regions, auditory cortex exhibited the most apparent signs of mild chronic inflammation as observed with protein increases in a microglia marker and activated astrocyte markers. These neuropathologic changes were concomitant with the auditory abnormality of this animal model. These findings suggest that the development and maintenance of the auditory system are also vulnerable to the inflammatory cytokine circulating in the pre- and peri-natal periphery. The pathologic link of the dopaminergic mal-development with the cortical specificity of inflammation remains to be illustrated, however.		3S7-2 Stress behaviors and the innate immune system in the brain Furuyashiki Tomoyuki Division of Pharmacology, Graduate School of Medicine, Kobe University Stress is a physical and psychological strain induced by aversive stimuli, and precipitates psychiatric disorders. Various kinds of stress in rodents, such as forced swim, restraint and social defeat, induce morphological changes in neurons of multiple brain areas, associated with emotional and cognitive changes. We and others reported that inflammation-related molecules are highly expressed in microglia and are critical for repeated stress-induced behavioral changes in mice. However, since none of these studies manipulated functions or gene expressions selectively in microglia, the direct evidence for a role of microglia in repeated stress-induced behavioral and neuronal changes is lacking. Whether and how repeated stress activates microglia also remains elusive. In chronic diseases associated with physical tissue damage, the concept of sterile inflammation has emerged, in which innate immune molecules, such as Toll-like receptors（TLRs）, sense cellular damage or stress to induce inflammation. Here we have shown that the loss of TLRs and their adaptor molecule MyD88 abolishes social avoidance induced by repeated social defeat stress in mice. TLRs and MyD88 are highly expressed in microglia, and the loss of TLRs impairs repeated stress-induced microglial activation as well as dendritic atrophy and attenuation of stress-induced response in prefrontal neurons. Furthermore, we developed methods to manipulate microglial functions in a brain region-specific manner, and have shown a causal role of TLR-mediated microglial activation in the prefrontal cortex in repeated stress-induced behavioral changes. In this symposium, I will highlight the importance of neuron-microglia crosstalk mediated by innate immune molecules in repeated stress, and will discuss the implications of these findings to therapeutic interventions of psychiatric disorders.

3S7-3 Neuroinflammation and sensation of fatigue Kataoka Yousuke RIKEN Center for life science Technologies Fatigue is defined as difficulty in initiating or sustaining voluntary activities, and is thought to be accompanied by deterioration of performance. Fatigue can be caused by many factors such as physical and mental stress, disturbance in the circadian rhythm, and various diseases. For example, following the flu or other types of infections, we experience a sense of fatigue that can last for days or weeks. The fatigue sensation is thought to be one of the signals for the body to suppress physical activity in order to regain health. The mechanism of induction of the fatigue sensation following viral infection has not been well understood. We obtained such a fatigue model in rats by administration of polyriboinosinic:polyribocytidylic acid (poly I:C), double-stranded RNA, which mimics viral infection. Intraperitoneal administration of poly I:C induced transient fever and suppression of locomotor activity in rats. The animals overexpressed interleukin (IL)-1β and IL-1 receptor antagonist in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v.) infusion of recombinant IL-1 receptor antagonist completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN)-α expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1 receptor antagonist prolonged recovery from suppression of spontaneous activity (PLOS ONE, 9, 2014). Our findings indicated that IL-1β is the key trigger of fatigue-like behavior and that IL-1 receptor antagonist prevents the neuroinflammation entering the chronic state. The balance of IL-1β and the endogenous antagonist in the brain possibly regulate neuroinflammation and fatigue sensation (Neural Regen. Res., 10, 2015). Although IL-1β is known to be produced mainly in microglia, cells engaging in suppression of neuroinflammation are poorly understood. We also discuss a new concept that glial progenitor cells maintain neuronal function by controlling local immune reactions and anti-apoptotic pathways.		3S7-4 Immaturity of the brain cells and mild chronic inflammation：Candidate endophenotype of neuropsychiatric disorders Miyakawa Tsuyoshi Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan Adequate maturation and integration of the adult-generated neurons into the circuit of the hippocampus would be crucial for normal cognitive functions and emotional behaviors. Disruption of the process could result in some disturbance in mental health. Previously, we reported that mice heterozygous for a null mutation of αCaMKII, a key molecule in synaptic plasticity, have profoundly dysregulated behaviors including hyper-locomotor activity and a severe working memory deficit, which are endophenotypes of schizophrenia and other psychiatric disorders. In these mice, almost all the neurons in the dentate gyrus（DG）of the mutant mice failed to mature at molecular, morphological and electrophysiological levels, causing severe deficit in the synaptic plasticity at mossy fiber-CA3 synapses. By using a simple real-time PCR assay using iDG markers, we identified five other strains of mutant mice that have a phenotype strikingly similar to iDG, including the forebrain specific calcineurin knockout mice, the mice lacking Neurogranin, a well-established schizophrenia susceptibility gene, and the mice lacking Schnurri-2, an NF-kappa B site-binding protein, that tightly binds to the enhancers of major histocompatibility complex（MHC）class I genes and inflammatory cytokines. We also found that chronic fluoxetine treatment or single pilocarpine administration can induce“dematuration”resulting in iDG-like phenotype in wild type mice. Most of the mice showing iDG-like phenotype seem to have increased adult neurogenesis in DG. Gene and protein expression patterns in the brains of these mice are strikingly similar to those found in the post-mortem brains of the patients of psychiatric disorders, such as schizophrenia and bipolar disorder. The brains of iDG mice show mild chronic inflammation, distinct from typical acute inflammation, as revealed by bioinformatics analyses of gene expression data. Anti-inflammatory drugs can reverse the iDG phenotype as well as some behavioral abnormalities in a subset of the mice showing iDG. I will discuss the potential implication of these findings in elucidating the pathophysiology of those neuropsychiatric disorders.