neurochemical alterations in medial prefrontal cortex of people with autism
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Abstracts / Neuroscience R
eurons induced excitatory presynaptic differentiation in contacting axons.L1RAPL1 also showed robust synaptogenic activity in vivo when transfectednto the cerebral cortex of developing mouse brain. On the other hand, injec-ion of recombinant extracellular domain of IL1RAPL1 into cerebral cortexindered spinogenesis of cortical layer 2/3 pyramidal neurons. These resultsuggest that IL1RAPL1 functions as a synaptogenic factor in the brain. Ourndings raise an intriguing possibility that the impairment of synapse forma-ion may underlie certain forms of MR and autism as a common pathogenicathway shared by these mental disorders.esearch fund: 22700392.
oi:10.1016/j.neures.2011.07.1756
4-s15 Dysregulation of NF-B signaling is involved in theathogenesis of a mouse model for Rett syndromeoriyuki Kishi 1,2 , Jeffrey D. Macklis 3, Hideyuki Okano 1,2
Department of Physiology, Keio University School of Medicine, Tokyo, JapanRIKEN-Keio University Joint Research Team, RIKEN Brain Science InstituteCenter for Nervous System Repair, Massachusetts General Hospital/Harvardedical School, Boston, USA
ett syndrome is a neurodevelopmental disorder and the second mostommon cause of mental retardation after Down syndrome in girls. The iden-ification in 1999 of mutation of the MECP2 gene on the X chromosome as theause of Rett syndrome enabled a new era of cellular and molecular analysisnd understanding of Rett syndrome pathophysiology. Based on our previ-us work, we pursued two complementary approaches for the identificationnd molecular analysis of target genes of MeCP2 in the callosal projectioneurons (CPN) of layer 2/3, using both microarray and chromatin immuno-recipitation (ChIP) approaches. One of the 18 over-expressed genes is Irak1,component of the NF-B signaling pathway. Quantitative RT-PCR confirmspproximately 3-fold overexpression in Mecp2-null CPN, and both ChIP anal-sis and bisulfite genomic sequencing identify that MeCP2 binds to one highlyethylated CpG in the promoter region, indicating that MeCP2 directly regu-
ates Irak1 in the brain. We performed multiple experiments that functionallyie Irak1 to central aspects of the MeCP2 loss-of-function phenotype. Over-xpression of Irak1 decreases dendritic arborization both in vitro and in vivo,imicking the phenotype in CPN of Mecp2-null mice. Importantly, reducingF-B signaling in Mecp2-null mice partially rescues the dendritic com-lexity phenotype and ameliorates their shortened lifespan. These results
ndicate that Irak1 is both a direct target of MeCP2 transcriptional regulation,nd that its over-expression is directly involved in the pathogenesis of Mecp2utant mice. We are now pursuing expression analysis of NF-B signaling-
elated genes using PCR arrays that can analyze expression changes of manyenes more precisely and reproducibly than microarrays. These approachesill not only reveal detailed molecular mechanisms of dysregulation of NF-B signaling in Rett syndrome model mice, but also potentially contribute to
uture therapeutic strategies.esearch fund: Funding Program for World-leading Innovative R&D on Sci-nce and Technology.
oi:10.1016/j.neures.2011.07.1757
4-s16 Neurochemical alterations in medial prefrontal cor-ex of people with autismuta Aoki 1 , Hidenori Yamasue 1,2, Osamu Abe 3, Nori-ki Yahata 1,4, Tatsunobu Natsubori 1, Norichika Iwashiro 1,osuke Takano 1, Hideyuki Inoue 1, Hitoshi Kuwabara 5, Yukiawakubo 5, Wataru Gonoi 6, Hiroki Sasaki 6, Mizuho Murakami 6,asaki Katsura 6, Yasumasa Nippashi 6, Hidemasa Takao 6, Akira
unimatsu 6, Hideo Matsuzaki 7, Kenji Tsuchiya 7, Kiyoto Kasai 1
Dept Psych, Univ of Tokyo, Tokyo, Japan 2 JST, CREST, Tokyo, Japan 3 Deptadiol, Nihon Univ Sch of Med, Tokyo, Japan 4 The GCOE, Univ of Tokyo, Tokyo,
apan 5 Dept Child Psych, Univ of Tokyo, Tokyo, Japan 6 Dept Radiol, Univ ofokyo, Tokyo, Japan 7 Osaka-Hamamatsu Joint Res Center for Child Mentalevelop, Hamamatsu Univ School of Med, Hamamatsu, Japan
ndividuals with autism show difficulties in theory of mind and social interac-ion with other peoples. Although previous functional neuroimaging studiesave repeatedly suggested an important role of functional abnormalitiesf medial prefrontal cortex (mPFC) in this deficit, neurochemical mecha-isms for the dysfunctional mPFC have not yet been elucidated. The present
tudy employed 1H-MR-spectroscopy (1H-MRS) obtained using 3-tesla MRIcanner and LCmodel to measure metabolites concentration of mPFC in 17igh-functioning medication-free adult males with ASD and 20 demograph-cally matched typically developed individuals. The subjects with ASD had
h 71S (2011) e108–e415 e401
trends for higher concentrations of metabolites than the TD controls in themPFC. We will show the results in larger study sample size at the meeting,The current study could provides an evidence of abnormal metabolites con-centration in mPFC which might plays an important role in disrupted theoryof mind in ASD subjects.
doi:10.1016/j.neures.2011.07.1758
P4-s17 Identification and characterization of interactingproteins of CDKL5, a gene product responsible for West syn-drome or atypical Rett syndromeKousue Okuda , Aya Watanabe, Masashi Mizuguchi, TeruyukiTanakaDept Developmental Medical Sciences, Univ of Tokyo, Tokyo, Japan
West syndrome is one of the most intractable epilepsy syndromes in infancy,and characterized by infantile spasms, abnormal EEG, profound mental andmotor development delay.Rett syndrome is a progressive neurodevelopmental disorder in femaleinfants, characterized by progressive loss of intellectual functioning, fineand gross motor skills and communicative abilities, and the developmentof stereotypic hand movements. Approximately 80% of the patients havemutations in X-linked methyl-CpG-binding protein 2 (MECP2) gene.Intriguingly, mutations in the cycline-dependent kinase-like 5 (CDKL5) gene onthe X chromosome have been identified in the patients with West syndromeor atypical Rett syndrome without mutations in the MeCP2 gene.CDKL5 is a member of the serine/threonine kinase family, with its N-terminalkinase domain sharing homology to the mitogen-activated protein (MAP)kinase and cycline-dependent kinase (CDK) families. The protein localizes inthe nucleus and the cytoplasm, which is considered to be mediated by theC-terminal region. However, it remains unknown how CDKL5 functions inthe nervous system.In order to identify the functional interactions of CDKL5, we performed theyeast two-hybrid screening assay. CDKL5 has the N-terminal kinase domainand the C-terminal region. Each domain was used as the bait. As the results,21 candidates were obtained, of which 19 were in the kinase domain and 2in the other domain.Furthermore, to confirm the CDKL5 interaction with each candidate, weperformed GST pull-down assay and in vitro kinase assays. As the results,interacting proteins and kinase substrates of CDKL5 in vitro were obtained.We will discuss the molecular and/or biochemical mechanisms of CDKL5interactions with these proteins at the meeting.Research fund: The Japan Epilepsy Research Foundation, H23 Research Grant,KAKENHI 21659252.
doi:10.1016/j.neures.2011.07.1759
P4-s18 Task-specific different hemodynamic response pat-terns in inhibitory control using NIRS between drug-naïveadults with autism spectrum disorder and with ADHDAyaka Ishii 1 , Yuki Kawakubo 2, Ryuu Takizawa 3, YukikaNishimura 3, Hitoshi Kuwabara 3, Yukiko Kano 2, Kiyoto Kasai 3
1 Pediatrics, Grad Sch of Med, Tokyo University, Tokyo, Japan2 Childpsychiatry, Grad Sch of Med, Tokyo University, Tokyo, Japan3 Psychiatry, Grad Sch of Med, Tokyo University, Tokyo, Japan
Introduction: Previous studies have reported prefrontal dysfunction duringinhibitory control in attention-deficit/hyperactivity disorder (ADHD) andautism spectrum disorders (ASDs), respectively, but direct comparison ofprefrontal activation between the two disorders have not been fully studied.Objective: To determine whether differences of brain activation duringinhibitory control in direct comparison between ADHD group and ASDs groupand examine a potential aid tool for differential diagnosis.Methods: Drug naïve 19 adults with ADHD, 20 adults with ASDs and 20 adultcontrols recruited mainly from The University of Tokyo hospital in Tokyometropolitan area. Prefrontal hemodynamic activations were assessed withnon-invasive and portable near infrared spectroscopy (NIRS).Results: Direct comparison between ADHD and ASDs adults analyses wereused to compare NIRS [Oxy-Hb] signal during stop signal task (SST).Results: Our multi-channel NIRS study using the SST had 2 principal findings:(1) During the SST condition: both ADHD and ASDs groups showed reduced
[Oxy-Hb] in the frontal pole, DLPFC, VLPFC, preSMA and PMA, relative tohealthy controls. (2) During the SST and post-SST condition, the significantdifferences between ADHD and ASDs group were localized in the left VLPFC.Even between ADHD and ASDs with ADHD symptoms, the significant differ-ence also remained in the left VLPFC.