公募シンポジウム

公募シンポジウム小児期愛着形成障害に起因する発達障がいのシナプス分子病態と治療

2B-公募-1 Neural basis of reactive attachment disorder：A functional and volumetric MRI study 友田明美福井大・子どものこころの発達研究センター Exposure to childhood adversity markedly increases the risk of developing mood, anxiety, personality, substance abuse and psychotic disorders. Recent studies suggest that clinical sequelae may stem, at least in part, from enduring adverse effects on brain development. The psychiatric consequences likely depend on genetic predisposition, and type and timing of exposure. Generally, early onset and longer duration of abuse have been associated with greater morphological change, but this may be an oversimplification. An alternative hypothesis is that stress-susceptible brain regions have their own unique sensitive periods（or windows of vulnerability）to the effects of early stress. Further, some of the adverse consequences of exposure to early stress may remain hidden until they are unmasked by subsequent maturational events. One negative outcome of child maltreatment can be a disorder of emotional functioning, reactive attachment disorder（RAD）, where the child displays wary, watchful, and emotionally withdrawn behaviors. Despite its clinical importance, little is known about the potential neurobiological consequences of RAD. Our research will be reviewed highlighting the effects of childhood maltreatment on the development of the visual cortex and ventral striatum in children with RAD. Evidence will be presented identifying sensitive periods when specific brain regions are most vulnerable to the effects of early stress.		2B-公募-2 WAVE1は脆弱X症候群の認知機能障害に関与する上江洲章吉¹，ニューファートーマス¹，ロドリゲスラモーナ²，ウェッスルウイリアム²，ソダリングスコット¹ ¹デューク大学，²デューク大学脆弱X症候群（FXS）は自閉症様症状、感覚障害、認知障害などを示す遺伝性の疾患であり、原因遺伝子Fmr1がコードするFMRP（fragile X mental retardation protein）の発現低下によって起こる。モデル動物であるFmr1ノックアウトマウスは学習・記憶障害などの表現型を示し、樹状突起棘の形態異常、代謝型グルタミン酸受容体の活性化による長期抑制（LTD）の亢進などが観察されている。RNA結合分子であるFMRPはタンパク翻訳を負に制御しているが、マウスモデルではシナプス関連タンパク質の翻訳亢進が認められ、病態の元になっていると考えられている。現在まで、mGluR5からFMRPに至る上流のシグナル伝達経路の亢進が明らかにされている一方で、800以上に登ると予想されるFMRPの標的RNAのうちFXS発症に関わる主要な分子群はどれか、どのようにFXSの病態に寄与するのか、に関する知見は乏しい。今回私たちはFMRPの標的分子として、アクチン結合タンパク質であるWAVE1を新たに見出した。WAVE1は突起棘のアクチン線維重合に関わり、その形態やシナプス可塑性を制御している。Fmr1ノックアウトマウスでは大脳皮質のWAVE1発現上昇が認められたが、WAVE1+/-マウスと交配することで正常化された。さらに、Fmr1ノックアウトの表現型である棘突起密度の増大やモリス水迷路試験での学習記憶障害などもWAVE1+/-マウスと交配することで正常化された。ただし聴原発作発現に変化は認められなかった。これらのことから、Fmr1ノックアウトマウスにおいてFMRPの標的分子のひとつWAVE1の過剰発現がFXSの一部表現型に関与すると考えられる。

2B-公募-3 PTSD-like behavior in FABP3 null mice and its improvement by melatonin agonist 福永浩司¹，矢吹悌¹，大和田裕二² ¹東北大院・薬・薬理学，²東北大院・医・器官解剖学［Background and Objective］Fatty acid binding protein 3（FABP3, H-FABP）binds to the intracellular loop of dopamine D2L receptor and FABP3 null mouse reveals dysfunction of dopamine-regulated motor coordination（J Neurosci 2010；30：3146）. We here documented that FABP3 null mouse also exhibits an enhanced anxiety and impaired memory extinction like post traumatic stress disorder（PTSD）. ［Methods］Wild type mice（C57BL6）and FABP3 null mice underwent fear conditioning once a day with consecutive 5 days and measured the fear acquisition and extinction for 35 days. When mice were administrated with melatonin receptor agonist, the drug was orally administrated once a day. ［Results］The acquisition of contextual fear memory in FABP3 null was not distinguished from those in wild type mice. However, FABP3 null mice had deficits in extinction of contextual fear memory. For example, in one month after exposure to contextual stimulation, wild type mice significantly revealed shortening of the elapsed time until entering the chamber given footshock. The elapsed time remained elevated in FABP3 null mice, suggesting the deficits in the extinction. Likewise, cFos expression in the amygdala after exposure to contextual stimuli remained elevated in FABP3 mice but declined in the wild type mice at one month later. The administration of melatonin receptor agonist completely improved PTSD-like behaviors in FABP3 null mice. ［Conclusion］FABP3 null mice are novel model of PTSD, which is rescued by melatonin. This work was supported by Kakenhi 26102704（K.F.）. The authors have no financial conflicts of interest to disclose concerning the presentation.		2B-公募-4 Disturbance of intracellular MTNR1A trafficking participates in autism spectrum disorders Han Feng¹，Hong Ling-Juan¹，Tian Yun¹，Wang Huijuan^1,2 ¹College of Pharmaceutical Sciences, Zhejiang University，²The Children's Hospital, Zhejiang University Autism spectrum disorders（ASDs）are a heterogeneous group of bio-neurological developmental disorders that display common behavioral symptoms. Increasing evidence indicates that pineal endocrine hypofunction and alterations in the melatonin pathway increase the susceptibility to autism. This study aimed to evaluate the role of melatonin/melatonin receptor subtype 1（MTNR1A）trafficking in autism spectrum disorders. We found that disturbances of the serine/threonine kinases signaling system, synaptic efficacy and autism-like social behavioral disorders in BTBR mice and valproic acid（VPA）animal model. Intriguingly, melatonin treatment attenuated the abarrencies in hippocampal CaMKII/PKA/PKC signaling, and this attenuation paralleled with appearance of autism-like behaviors in VPA-treated rats. Furthermore, we applied biochemical, fluorescence resonance energy transfer（FRET）and electrophysiological techniques to characterize the effect of VPA on MTNR1A internalization in its agonist-activated state. Our findings indicate that the disassociation between MTNR1A and β-arrestin 2 underlies the VPA-mediated inhibition of intracellular MTNR1A trafficking and signaling. Taken together, novel therapies that relieve the disturbance of melatonin-mediated MTNR1A intracellular trafficking may help lower the risk of autism spectrum disorders.