Symposium
Roles of epigenetics and inflammation in mental illness
シンポジウム
精神疾患におけるエピゲノムと炎症の役割 |
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| 7月25日（木）9:03～9:31 第2会場（朱鷺メッセ 2F メインホールA）
1S02m-1
Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mice
Zhen Yan（Yan Zhen）
State Univ of New York at Buffalo
Haploinsufficiency of the SHANK3 gene, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism
spectrum disorder (ASD). Genetic studies of autism patients also identified histone modifiers and chromatin remodelers as the
most prominent ASD risk factors. Here, we found that brief treatment with romidepsin, a highly potent class I histone
deacetylase (HDAC) inhibitor, alleviated social deficits in young Shank3-deficient mice, which persisted for ~3 weeks. HDAC2
transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits.
Nuclear translocation of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in
Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin
treatment elevated the expression and histone acetylation of Grin2a and actin regulatory genes, and restored NMDAR function
and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying
social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3
mutations. | | 7月25日（木）9:31～9:59 第2会場（朱鷺メッセ 2F メインホールA）
1S02m-2
神経細胞におけるゲノム・エピゲノムの多様性と精神疾患
Kazuya Iwamoto（岩本 和也）1，Miki Bundo（文東 美紀）1,2，Tadafumi Kato（加藤 忠史）3
1熊本大院生命科学・分子脳科学
2JSTさきがけ
3理研脳セ・精神疾患動態
Bipolar disorder and schizophrenia are severe psychiatric disorders with unknown etiology. Although recent genome-wide association studies suggest that the genetic factors with small effect sizes collectively contribute to their pathophysiology, underlying molecular mechanisms, especially how environmental factors interact with genetic factors and lead to the altered brain function in patients, remain largely unknown. Accumulating evidence suggests that genomic DNA in the neuronal cells exhibit genetic and epigenetic variations. These include somatic mutations such as SNV/CNV, chromosomal aneuploidy and dynamics of retrotransposition for the genetic variations, and various cytosine modifications such as methylation and hydroxymethylation for the epigenetic variations. Currently, we identified the altered LINE-1 retrotransposition activity in neuronal genome of patients with schizophrenia, and neuronal cell-type specific, pathophysiology-related DNA methylation changes in prefrontal cortex of bipolar disorder. We discuss altered frequencies and patterns of these variations may have pathophysiological consequence of these disorders. Further genetic and epigenetic analyses in the brain genome will contribute to understand the pathophysiology of psychiatric disorders. | | 7月25日（木）9:59～10:27 第2会場（朱鷺メッセ 2F メインホールA）
1S02m-3
ストレスによる情動変容を担う脳内局所炎症反応：エピゲノム制御の関与の可能性
Tomoyuki Furuyashiki（古屋敷 智之）
神戸大院医薬理
Excessive or prolonged stress caused by aversive stimuli induces emotional and cognitive disturbances, and can be a risk factor for mental illnesses. Using rodent stress models, roles and actions of neural inflammation for stress-induced behavioral changes have been examined. Our group has recently demonstrated that repeated social defeat stress in mice induces microglial activation in the medial prefrontal cortex through innate immune receptors TLR2/4, and consequently causes structural atrophy of prefrontal neurons and depression-like behavior. Notably, using immunohistochemistry for microglial activation markers, we found that this stress-induced activation of prefrontal microglia is augmented with repetition of the stress, suggesting priming of prefrontal microglia. Since priming of macrophages with repeated TLR stimulation is thought to involve epigenetic mechanisms with histone modifications, we currently investigate how social defeat stress alters epigenetic profiles of prefrontal microglia and whether such epigenetic alteration underlies repeated social defeat stress-induced priming of prefrontal microglia as well as concurrent neuronal and behavioral changes. Our preliminary findings using brain region- and cell type-specific ChIP-seq reveal that repeated social defeat stress alters epigenetic profiles of prefrontal microglia in a manner partly related to individual variability of stress susceptibility. In this symposium, I will introduce our recent findings about social defeat stress-induced local inflammatory responses in the brain for emotional changes and discuss possible relevance of epigenetic regulation in priming and maintenance of these responses. | | 7月25日（木）10:27～10:55 第2会場（朱鷺メッセ 2F メインホールA）
1S02m-4
精神疾患患者の血液を用いたミクログリア仮説解明のための橋渡し研究
Takahiro A. Kato（加藤 隆弘），Masahiro Ohgidani（扇谷 昌宏），Shigenobu Kanba（神庭 重信）
九州大 院医 精神病態医学
Microglia, immune cells in the CNS, have recently been highlighted to understand the underlying pathophysiology of chronic pain and various neuropsychiatric disorders including schizophrenia, mood disorders and autism spectrum disorder. Postmortem brain analysis and PET imaging analysis are two major methods to estimate microglial activation in human subjects, and these studies have suggested activation of human microglia in the brain of patients with various psychiatric disorders. However, by using the above methods, only a limited aspect of microglial activation can be measured. Dynamic analysis using fresh microglia in human brain is an ideal method, however technological and ethical considerations have limited the ability to conduct research using fresh human microglia. Thus, alternative methods using non-brain tissues are warranted.
To overcome this limitation, we have originally developed a technique to create directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes adding GM-CSF and IL-34 for 2 weeks, instead of brain biopsy (Ohgidani et al. Sci Rep 2014). Using the iMG cells, dynamic morphological and molecular-level analyses such as phagocytosis and cytokine releases are applicable.
We have used the iMG cells as surrogate cells of human microglia, and revealed previously-unknown dynamic pathophysiology of microglia in patients with Nasu-Hakola disease (Ohgidani, Kato et al. Sci Rep 2014), fibromyalgia (Ohgidani, Kato et al. Sci Rep 2017) and rapid-cycling bipolar disorder (Ohgidani, Kato et al. Front Immunology 2017). The iMG cells can reveal both state- and trait- related microglial characteristics of human subjects by repeated analysis, and we believe that the iMG technique sheds new light on clarifying dynamic molecular pathologies of microglia as surrogate markers of human microglia in a variety of neuropsychiatric disorders.
In addition, we have recently shown microglia-related pathophysiology using plasma analysis such as human metabolome analysis focusing on the tryptophan-kynurenine pathway (Kuwano, Kato, Setoyama et al. J Affect Disord 2018 April) and neuron-related exosome analysis (Kuwano, Kato, Mitsuhashi et al. J Affect Disord 2018 Nov).
We believe that these indirect methods shed new light on clarifying dynamic molecular pathologies of microglia in a variety of neuropsychiatric disorders. | |
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