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1L1 an Outsider S Take on Autism Spectrum Disorders

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1L1 an Outsider S Take on Autism Spectrum Disorders Plenary Lecture 特別講演 1L1 An outsider’s take on autism spectrum disorders ○Martin Raff MRC LMCB, University College London Autism spectrum disorders（ASDs）are among the commonest neuropsychiatric disorders. Although, until re- cently, ASDs were one of the least understood of these disorders, they are now one of the best understood. Pro- gress has come largely through recent advances in human genetics that have identified rare large!effect muta- tions that cause or greatly increase the risk of these disorders, together with studies of genetic mouse models based on these mutations. Remarkably, in a number of mouse models caused by single mutations, correction of the problem in the adult brain（with either drugs or genetic manipulations）largely reverses many of the behav- ioral and neurobiological abnormalities, providing hope for the development of therapies for individuals with ASDs. In my talk, I will review the basic features of ASDs, using home videos of the development of my 13!year! old autistic grandson as an example, and I will discuss some of the recent advances in ASD research, consider current puzzles, and speculate on possible ways forward. Plenary Lecture 特別講演 2L1 A role of drebrin A in the activity!dependent trafficking of NMDA receptors to the plasma membrane ○Chiye Aoki1，Sho Fujisawa1，Kei Tateyama1，Yi!Wen Chen1，Tomoaki Shirao2 1Center for Neural Science, New York University 2Dept of Neurobiology and Behavior, Gunma Univ Graduate School of Medicine NMDA receptors（NMDARs）are central molecular agents that enable the activity!dependent modification of synaptic strengths at excitatory synapses. However, relatively little is known about the molecular mechanisms regulating NMDAR levels at each synapse. We have previously used electron microscopic（EM）immunocyto- chemistry（ICC）to quantify the NMDAR levels at dendritic spines and to further differentiate the proportion of NMDARs occurring specifically at the plasma membrane, where they can bind to ligands, versus the cytoplasm, reflecting their reserve pools. In 2003, we demonstrated that this approach can successfully capture the activity! dependent trafficking of NMDARs from the dendritic shaft into the spine cytoplasm and to the plasma mem- brane following 30 min exposure of intact pyramidal neurons within cerebral cortex to the NMDAR antagonist, D!APV. We hypothesized that decreased activation of synaptic NMDARs by D!APV may increase NMDAR trafficking to the plasma membrane by promoting the tethering of NMDAR!containing saccules along the F!ac- tin lattice. What might be the molecular agent that translates synaptic activity to the F!actin!mediated traffick- ing of NMDARs? Drebrin A is a good candidate to be this agent, because drebrin A finds to F!actin and is traf- ficked more into the spine head in response to D!APV blockade. This idea was tested by subjecting cortices of mice with global KO of drebrin A to D!APV blockade. Drebrin A KO cortices failed to up!regulate the NMDAR level at the plasma membrane within the hemisphere treated with D!APV, relative to the vehicle!treated hemi- sphere（0％ ± 13％ increase［mean±SEM］）, while the WT cortices up!regulated NMDAR levels at spines 94％ ± 28％ following D!APV treatment, relative to the vehicle!treated side. Comparisons of spine head size and NMDAR levels at spines of vehicle!treated hemispheres comparisons did not reveal any difference across the KO!WT genotypes, suggesting that drebrin A is involved in the activity!dependent regulation of synaptic strength, rather than their basal levels. Plenary Lecture 特別講演 3L1 Genetically encoded tools for brain analysis ○Atsushi Miyawaki（宮脇 敦史） RIKEN Brain Science Institute RIKEN Center for Advanced Photonics（理化学研究所 脳科学総合研 究センター 光量子工学研究領域） The striking progress in genome science and gene technology has led to numerous discoveries and the rapid de- velopment of new technologies in the life sciences. These new technologies include“optogenetics”―a growing suite of techniques that combine optical and molecular genetic methods. The technologies employ genetically en- coded tools and are becoming popular particularly in neuroscience, where the central challenge is to understand the mechanisms by which neurons process and integrate synaptic inputs and how these mechanisms are modi- fied by activity. Since the isolation of the green fluorescent protein from the bioluminescent jellyfish in 1992 and the subsequent development of related molecules from non!bioluminescent marine animals, genetically encoded sensors that en- able fluorescence imaging of excitable cell activity have been constructed by fusing fluorescent proteins to func- tional proteins that are involved in physiological signaling. Because these sensors can be introduced by gene transfer techniques, they may extract neuronal signals from an intact brain more efficiently than conventional organic dyes. Also, their expression is driven in a certain population of neurons by the use of a specific pro- moter；this has made visualization of the connectivity between two or more different（sub）populations of neu- rons all the more exciting. On the one hand, many genetically encoded sensors have been developed to investigate the function of specific signaling mechanisms in synaptic transmission, integration, and plasticity. The sensors that monitor signals re- sulting from electrical activity, such as free!Ca2＋ concentration and pH, instead of transmembrane voltage, func- tion as low!pass filters. On the other hand, optogenetic control of neuronal activity allows us to selectively acti- vate or inactivate genetically defined populations of neurons in order to examine how the activity of these neu- rons contributes to the function of neural circuits in the brain. Due to recent remarkable progress in gene trans- fer techniques, including electroporation, virus!mediated gene transfer, and germline transmission of transgenes, the experimental animals to be studied are not limited to mice but extended to primates. Newly emerging geneti- cally encoded tools will surely stimulate the imagination of many neuroscientists, and this is expected to spark an upsurge in the demand for them. 1L2 Therapeutic strategy for brain disorders as 1L3 Oxytocin and more：what we have learned systemic diseases from the brain development and its disor- ders ○Keiji Wada（和田 圭司） National Institute of Neuroscience, National Center of Neurol- ○Makoto Sato1,2,3（佐藤 真） ogy and Psychiatry（国立精神・神経医療研究センター神経研 1Department of Anatomy and Neuroscience, Osaka Univer- 究所） sity Graduate School of Medicine（大阪大学大学院医学系研究 科生命機能研究科），2United Graduate School of Child Devel- In this talk, changes of conceptual framework of neurodegen- opment, Osaka University（大阪大学 連合小児発達学研究 erative disorders are reviewed and new therapeutic strate- 科），3Research Center for Child Mental Development, Uni- gies are discussed for the disorders. Historically, neural cell versity of Fukui（福井大学 子どものこころの発達研究セン death was the hallmark for diagnosing neurodegenerative ター） disorders. Besides the cell death, in recent years, neuronal cell dysfunction has received more attention in pathophysi- Autism spectrum disorders（ASD）is not a sole disorder but ological aspects of the disorders. Studies of glial cells raised a group of disorders, which is characterized by persistent importance of their contribution in neural information proc- deficits in social communication and social interaction as well esses, and a tripartite synapse hypothesis became a hot topic as restricted, repetitive patterns of behavior and!or inter- " in neuroscience. More recently, prionoid spreading hypothe- ests. So far, there exist no verified treatments for ASD. Oxy- " sis of disease causing molecules attracted a great deal of at- tocin has attracts much attention for its potential as a new tention, which has led, for example, to a wave of exsosome pharmacological treatment for ASD. Several studies demon- analyses of fluid samples from patients. On the other hand, in- strated that an application of a single"dose of oxytocin nasal volvements of the immune system and metabolism in the on- spray results in an improvement of the social communication set of neurodegenerative disorders were studied even before of ASD patient for a while, but whether a continuous oxyto- the modern molecular biology was introduced in science. cin application has pro"longed therapeutic effects or not re- Clinically, in addition to core symptoms, associated symp- mains open. Our Research Center for Child Mental Develop- toms（for example, behavioral and psychological symptoms in ment at University of Fukui found that such continuous ap- dementia）are cues for clinical treatment of neurodegenera- plication is effective for a limited group of patients. This ob- tive disorders. Biomarkers for Parkinson’s disease could be servation reinforced the concept that ASD is a mixture of detected outside the brain, for example, using the cardiac disorders of which etiologies are varied. To elucidate such scintigraphy method. Based on these trends, it is quite rea- etiologies, we examined the role of specific neurons, of which sonable the idea of systemic disorders occurring in neurode- function is likely to be involved in ASD characteristics as " " generative disorders. Accordingly, brain other organ net- well as neural networks. In my talk, I will also introduce our works become important when considering the targets for recent attempts of such studies. clinical intervention of the disorders. Thus, therapeutic strategies must be reconsidered in the aspect that neurode- generative disorders
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