Symposium

Symposium 20 Neuronal calcium pathology of mental disorders シンポジウム20 精神障害の神経細胞内カルシウム病態

SY20-1 Deciphering a calcium-regulated pathway that controls radial migration of immature cortical neurons 大脳皮質放射状神経細胞移動を制御するカルシウム依存的分子経路の解明 Horigane Shin-Ichiro（堀金慎一郎）^1,2,3，竹本―木村さやか^1,2,3,4，上條諭志³，安達―森島亜希³，藤井哉³，尾藤晴彦³ ¹Dept. of Neurosci. 1, Res. Inst. of Environme, Nagoya Univ., Nagoya-Shi, Japan ²Mol. cell. neurosci., Nagoya Univ. Grad. Sch. of Med., Nagoya-shi, Japan ³Dept. of Neurochemistry, Grad. Sch. of Medicine, The Univ. of Tokyo, Tokyo, Japan ⁴Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama, Japan It is believed that abnormality in circuit formation is a risk factor for psychiatric disorders, and thus, the molecular basis of circuit formation is being intensively studied. Neuronal migration is indispensable to establish brain architecture and neuronal circuits. Several genes involved in neuronal calcium signaling are considered neuropsychiatric disorder-related, but whether and how they regulate neuronal migration remains to be elucidated. To uncover the role of Ca²⁺ signaling in radial migration, we examined the intracellular Ca²⁺ dynamics of migrating neurons using GCaMP6s. We show that migrating neurons repeatedly display intracellular Ca²⁺ transients and Ca²⁺ events happen more frequently during slow and deceleration periods. In order to elucidate the molecular mechanisms underlying these Ca²⁺ transients, we performed pharmacological studies, and found that the pharmacological induction of Ca²⁺ transients impairs radial migration. We are currently characterizing further downstream Ca²⁺-regulated events, especially phosphorylation, that ultimately control important aspects of radial migration. Taken together, our findings suggest that the Ca²⁺-dependent phosphorylation pathway governs cortical radial migration, and that dysregulation of Ca²⁺ signaling may lead to aberrant cortical circuit formation.		SY20-2 Contribution of calcium signaling related-gene variants to mental disorders カルシウム関連遺伝子変異の精神障害への関与 Aleksic Branko，Wang Chenyao，尾崎紀夫 Nagoya University Graduate School of Medicine There is currently a great deal of interest in voltage-gated calcium channels, with regard to their involvement in the genesis of a spectrum of psychiatric disorders; particularly autism spectrum disorder, schizophrenia, and bipolar disorder. Genetic analyses of large patient cohorts have identified loci associated with the risk of mental illnesses including schizophrenia, autism spectrum disorder and bipolar disorder. Several of these candidate risk genes encode proteins involved in calcium signaling, including voltage gated calcium channel subunits that may ultimately converge on a common disease mechanism. To further examine the association between calcium channels genes and SCZ/ASD development, we conducted a mutation screening study of several calcium channel related genes to identify rare mutations that potentially cause diseases, in SCZ and ASD patients. This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls. We identified several rare missense mutations through the mutation screening. Although no statistically significant association between any single mutation and SCZ or ASD was found, several were found only in the patient group. To further examine the association between candidate variants and SCZ or ASD development, a larger sample size and functional experiments are needed.

SY20-3 Possible role of mitochondrial Ca²⁺ signaling in serotonergic dysfunction in bipolar disorder: From analysis of Ant1 mutant mice 双極性障害におけるミトコンドリアCa²⁺シグナルとセロトニンの関係～Ant1変異マウスの解析から Kato Tadafumi（加藤忠史） Lab for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science In bipolar disorder, serotonergic dysfunction and mitochondrial dysfunction are implicated, but their relationship is unknown. A family of bipolar disorder and mitochondrial disease caused by a mutation of ANT1 was reported (Siciliano et al, Neuromuscular Disord 2003). ANT1 (adenine nucleotide translocator 1、SLC24A4) has a modulatory role for mitochondria permeability transition pore (mPTP). In this study, we found two patients with bipolar disorder carrying loss-of-function mutations of ANT1. To investigate the role of ANT1 in pathophysiology of bipolar disorder, we generated neuron-specific mutant mice of Ant1. Mitochondria isolated from the brain of mutant mice had reduced calcium retention capacity. Behavioral analyses showed that the mutant mice showed reduced delay discounting, suggesting altered serotonergic activity. Immuno-histochemical analysis of COX (cytochrome c oxidase) and SDH (succinate dehydrogenase) showed that COX-negative cells were accumulated in dorsal raphe neurons. Serotonin turnover was enhanced in nucleus accumbens and Maob mRNA was upregulated in dorsal raphe of mutant mice. Electrophysiological analysis showed hyperactivity of serotonergic neurons. These findings suggest that the Ant1 mutation may cause altered Ca²⁺ regulation in dorsal raphe neurons, where age dependent mitochondrial dysfunction is accumulated, and this may play a role in pathophysiology of bipolar disorder. A recent study using iPS cells derived from patients with bipolar disorder showed that mitochondrial dysfunction can cause hyperexcitability (Mertens et al, Nature 2015). The present study suggests that hyperexcitability of serotonergic neurons may play a role in bipolar disorder.		SY20-4 Calcium signaling in stress-related psychiatric disorders ストレス関連精神疾患におけるカルシウムシグナリングの役割 Uchida Shusaku（内田周作） SK Project, MIC, Kyoto Univ. Grad, Sch. Med. Chronic stressful life events during adulthood are potent adverse environmental factors that can activate or amplify the expression of depression symptoms. Many individuals exposed to stressful events do not show signs or symptoms of depression; however, some individuals exposed to psychological stress are predisposed to major depression. Thus far, the molecular mechanisms underlying the susceptibility and resilience to chronic stress within the brain are poorly understood. Modern views on the cause of depression suggest that the neural activities of specific brain circuits are altered in response to external stimuli, such as stress, as a result of maladaptive molecular and cellular changes. Neuronal activity regulates a complex program of gene expression that is involved in the structural and functional plasticity of the brain. There is also increasing evidence indicating that aberrant transcription regulation is one of the key components in the pathophysiology of depression. Recent reports have suggested that the epigenetic regulation of genes, such as DNA methylation and histone modification, can trigger the development of stress vulnerability. This dysregulation of epigenetic mechanisms could manifest through alterations in stress-response, which is tightly coupled to the actions of intracellular calcium. In this symposium, I will present the integration of previous findings and our ongoing studies suggesting an important role of calcium-binding proteins and related molecules in the development of stress vulnerability/resilience and in the pathophysiology of depression.