疾患モデル動物
Animal models
O2-9-4-1
Ntrk3(TrkC)の前脳背側に限局した欠損による記憶機能と不安様行動の変化
Memory functions and anxiety-like behaviors are altered by pallium-restricted ablation of Ntrk3 (TrkC)

○高嶋記子1, 赤木巧2, 小高由梨1, 有賀純1
○Noriko Takashima1, Takumi Akagi2, Yuri Odaka1, Jun Aruga1
理研・BSI・行動発達障害1, 理研・BSI・研究基盤2
Behavioral and Developmental Disorders, RIKEN BSI, Wako, Japan1, Support Unit for Animal Resources Development, RIKEN BSI. Wako, Japan2

Trk receptors are a family of three tyrosine kinases, each of which can be activated by one or more neurotrophins. Recent studies showed that allele variants of NTRK3 (also known as TrkC) are susceptibility factors for anxiety disorders and that rodent Ntrk3 can act as an excitatory synapse organizer. To clarify the role of Ntrk3 in vivo, we carried out spatially restricted gene targeting because the complete deficiency of Ntrk3 results in postnatal lethality. The mutant mice lacking Ntrk3 in pallium-derived structures (parts of cerebral cortex, hippocampus, and amygdala) were characterized behaviorally and morphologically. Systematic behavioral analysis revealed spatial memory acquisition deficit, enhanced cue-dependent fear memory and anxiety-like behaviors without any obvious abnormalities in sensory function and motor coordination. Multilevel morphometric analysis (magnetic resonance imaging, Golgi staining, and electron microscopic) revealed a significant change in the hippocampal synapse morphology. These results suggest that Ntrk3 has critical roles in the neural circuits controlling spatial memory and emotional behaviors presumably by maintaining synaptic integrity. Further investigation of the Ntrk3 conditional knockout mice would be beneficial to better understand the pathophysiology of anxiety disorders.
O2-9-4-2
内因性カンナビノイド2アラキドノイルグリセロールは歯状回の興奮性シナプス伝達を抑制し発作を抑制する
Suppression of excitatory synaptic input to the dentate gyrus and amelioration of seizures by the endocannabinoid 2-arachidonoylglycerol

○菅谷佑樹1, 山崎真弥2, 崎村建司2, 狩野方伸1
○Yuki Sugaya1, Maya Yamazaki2, Kenji Sakimura2, Masanobu Kano1
東京大学大学院 医学系研究科 神経生理学1, 新潟大学 脳研究所 細胞神経生物学2
Dept Neurophysiol, Univ of Tokyo, Tokyo1, Dept Cellular Neurobiology, Brain Research Institute, Niigata University2

It has been reported that more than 30 percent of patients with epilepsy have intractable seizures. Previous studies demonstrated that endogenous cannabinoids (endocannabinoids) caused retrograde suppression of excitatory synaptic transmission in the hippocampus during kainate-induced seizures and prevented further development of seizures. However, it is unclear which of the two major endocannabinoids suppresses seizures and how endocannabinoid signaling changes excitability in the hippocampus during seizures. We have recently demonstrated that 2-arachidonoyl glycerol (2-AG) produced by diacylglycerol lipase α (DGLα) is the endocannabinoid that mediates retrograde synaptic suppression. The present study aimed at elucidating roles of 2-AG during seizures in the hippocampal dentate gyrus. Under urethane anesthesia (1.75g/kg BW, i.p.), a stimulus electrode was implanted into the angular bundle of adult DGLα knockout mice and wild-type littermates. A 16-channel silicon probe was implanted into the dentate gyrus. Current source density in the dentate gyrus was calculated from local field potentials. We found that current sink around the inner molecular layer of the dentate gyrus was significantly larger after a perforant path stimulus in DGLα knockout mice than in wild-type littermates. There was no significant difference between the 2 genotypes in the level of current sink around the middle and outer molecular layer of the dentate gyrus after a perforant path stimulus. Seizures evoked by burst stimuli (20 Hz for 10 seconds) to perforant path were significantly longer in DGLα knockout mice than in wild-type littermates. Furthermore, current sink around the inner molecular layer of the dentate gyrus was significantly larger during seizures in DGLα knockout mice than in wild-type littermates. These results suggest that 2-AG suppresses excitatory inputs around the inner molecular layer and ameliorates seizures in the dentate gyrus.
O2-9-4-3
甲状腺受容体欠損マウスにおける行動および生化学的変化について
Behavioral and Biochemical alterations in thyroid hormone receptor deficient mice

○金井裕彦1, 大久保雅則1,2, 吉村篤3, 定松美幸4, 加藤進昌6, 鈴木悟5, 山田尚登1
○Hirohiko Kanai1, Masanori Ookubo1,2, Atsushi Yoshimura3, Miyuki Sadamatsu4, Nobumasa Kato6, Satoru Suzuki5, Naoto Yamada1
滋賀医大・精神1, 水口病院2, 西濃病院3, 金城学院大学人間科学部 多元心理学科4, 信州大学老年内科講座5, 昭和大学医学部精神医学教室6
Dept. Psychiatry, Shiga Univ. Med. Sci., Shiga, Japan1, Dept. Psychiatry, Minakuchi Hosp., Koka City, Japan2, Dept. Psychiatry, Seino Hosp., Ogaki City, Japan3, Dept. Department of Psychology, Human Sciences, Kinjo Gakuin University, Japan4, Dept. Aging Med. and Geriatrics, Shinshu Univ., Nagano, Japan5, Dept. Psychiatry, Showa Univ. Tokyo, Japan6

Thyroid hormone receptors (TRs) play multiple roles in the development of the central nervous system. Neonatal hypothyroidism and/or a genetic disruption of TRs can cause permanent behavioral impairments in both humans and animal models. Emerging evidence indicates that the TRs signaling during the neonatal period has a distinct role in the pathogenesis of neurobehavioral abnormalities, such as attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine the specific behavioral and biochemical alterations related to two functional types of TRs, TRα and TRβ, using young mice of various TRs genotypes. The tissue concentrations of monoamines and their metabolites were determined using HPLC in several regions of the mesolimbic and nigrostriatal systems. The regional alterations in specific proteins associated with histone modification, including acetylated histone H3 and histone deacetylases (HDACs), were subsequently measured. As a result, TRβ-deficient mice display hyperactivity with less habituation in the open field test. In contrast, hypoactivity was observed in double knockout mice (DKO). The dopamine metabolism in the caudate/putamen (Cpu) commonly decreased in all types of mutant mice. However, while the serotonin metabolism in the Cpu, amygdala (Amy) and hippocampus were decreased in TRβ deficient mice, the metabolism increased in DKO. Moreover, while the HDAC expression levels in the Amy and histone acetylation in the Cpu increased in TRβ deficient mice, they decreased in DKO. In conclusion, these biochemical and behavioral profiles suggest that TRα and TRβ signals are influenced in different ways. These distinct behavioral changes presume to be associated with the alterations in the dopaminergic and serotonergic tone as well as the epigenetic modulations in the mesolimbic and nigrostriatal systems of developing mice.
O2-9-4-4
近視難聴合併症原因遺伝子SLITRK6の網膜および内耳神経回路形成における役割
The roles of SLITRK6, a causal gene for myopia-deafness comorbidity, in retinal and inner ear neural circuit formation

○有賀純1, 松本圭史1, 佐郡和人1, 小田川摩耶1, 小高由梨1
○Jun Aruga1, Yoshifumi Matsumoto1, Kazuto Sakoori1, Maya Odagawa1, Yuri Odaka1
理研・脳セ・行動発達障害1
Lab Behav Dev Disord, RIKEN BSI, Wako, Japan1

Myopia is by far the most common human eye disorder, which is known to have a clear albeit poorly defined heritable component. Recently we and foreign collaborators described a new autosomal recessive syndrome characterized by high myopia and sensorineural deafness. The syndrome was found in three independent families, each of which included a homozygous nonsense mutation (p.R181X, p.S297X, or p.Q414X) in SLITRK6, a leucine-rich repeat domain transmembrane protein (Mustafa et al., J. Clin. Invest. in press). Transfection with wildtype and all three mutant molecules revealed a profound effect of the mutation on the abilities of SLITRK6 to induce synapse formation and to regulate neurite extension and number, consistent with a loss of SLITRK6 function. High resolution MRI of wildtype and Slitrk6-deficient mice eyes revealed axial length increase in the mutant (the endophenotype of myopia) and the mutant mice are known to show auditory function deficits, mirroring the human phenotype. Histological investigation of wildtype and Slitrk6-deficient mouse retina in postnatal development indicated a delay in synaptogenesis in Slitrk6-deficient animals implicating SLITRK6 in this process. Taken together our results show that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice. Detailed analysis on the neural circuit abnormalities is in progress to further understand the molecular functions of Slitrk6.
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