- Email: [email protected]
Morphological change of dorsal raphe nucleus in rats prenatally exposed to valproic acid: Serotonin neurons in animal models of autism
e76
Abstracts / Neuroscience Research 71S (2011) e46–e107
in 1–4% in ASDs. We made the genetically modified mice with a duplication of chromosome 7B-C that is orthologous to human chromosome 15q11–13 using a Cre-loxP mediated chromosome engineering technique. Behavioral battery tests, including 3-chambered social interaction test, reversal learning tasks, and ultrasonic vocalization tests showed mice with paternally inherited duplicated-chromosome (patDp/+) have behavioral abnormalities with poor social interaction, behavioral inflexibility, and developmentally delayed ultrasonic vocalizations that might recapitulate some aspects of autistic symptoms. Previous reports suggest serotonin (5-HT) is the most intriguing neurochemical molecule in ASDs. The 5-HT content in the brains of patDp/+ mice was globally reduced compared with that in wild type mice especially in the postnatal developmental ages. The patDp/+ mouse is regarded as a new model for ASDs because it displays not only behavioral but also genetic similarities with ASDs. Alteration in serotonergic signaling may contribute to autistic like abnormal behaviors. Research fund: JST, CREST. doi:10.1016/j.neures.2011.07.322
O3-G-1-3 Morphological change of dorsal raphe nucleus in rats prenatally exposed to valproic acid: Serotonin neurons in animal models of autism Akiko Oyabu , Takahiro Oyama, Kensaku Ujihara, Michiru Eto, Takeshi Ohkawara, Yasura Tashiro, Masaaki Narita Dept. Dev. and Regenerative Med., Mie Univ., Grad. Sch. of Med., Tsu, Japan The abnormal serotonergic system has been implicated in autism. Although the serotonergic system appears to be developmentally dysregulated in autism, its differentiation during prenatal development is poorly understood. To elucidate the morphogenesis of serotonergic neurons in animal models of autism, we have examined their distributions and axonal tracts in the embryonic hindbrain. Pregnant rats were also exposed to valproic acid (VPA) at embryonic day (E) 9.5, and their embryos at E14.5 and E15.5 were used. The hindbrain was dissected form the embryos, cut along the dorsal midline, opened and whole mounted with ventricular side downwards, which enabled us to observe the whole hindbrain without reconstructing the serial sections. Immunostaining with anti-serotonin antibody showed that the serotonergic neurons were localized to two discrete groups within the hindbrain, medial raphe nucleus (MRN) and dorsal raphe nucleus (DRN). At E14.5, the descending axons from MRN in autism model rats were shorter than those in control. On the other hand, there was no major difference between the descending axons from MRN in models of autism and those in control at E15.5. While DRN neurons in control extended from nearby floor plate to middle of pontine primordium at E14.5, those in animal models of autism located nearby floor plate. In particular, caudal DRN neurons in models of autism maintained to locate nearby floor plate and the abnormal morphology became prominent at E15.5. Thus morphology of serotonergic neurons at E14.5 and E15.5 has already been affected by prenatal VPA exposure. Our findings indicate that disruption of early serotonergic neural development might be involved in the etiology of autism. doi:10.1016/j.neures.2011.07.323
O3-G-1-4 The modulation of neuronal morphology by the interaction between a mental retardation gene, motopsin/neurotrypsin, and seizure related gene (Sez)-6 Shinichi Mitsui , Kazunari Yuri Dept. Neurobiol. & Anat., Kochi Med. Sch., Nankoku, Japan Motopsin is a neuron-specific serine protease, which is composed of a proline-rich domain, a kringle domain, three SRCR domains and a protease domain at the C-terminal. The loss of motopsin function causes severe mental retardation in human and enhances social interaction, but without learning deficit, in mouse. The mosaic structure of motopsin protein suggests that it interacts to other molecules. So we performed an yeast two-hybrid screening against a mouse fetal brain cDNA library and identified Sez-6, which is known to modulate dendritic arborization and synaptogeneis, as a motopsininteracting protein. A two-hybrid analysis and a pulldown assay suggest that the proline-rich and kringle domains of motopsin bind SCR domains of Sez6. When motopsin and Sez-6 were transiently expressed in a neuroblastoma cell lines, neuro2a, both proteins were co-precipitated. Motopsin and Sez-6 were co-localized in primary hippocampal cultured neurons. Immunohistochemical analysis revealed P10 mouse cortical neurons co-expressed both proteins. Further, the expression of motopsin in neuro2a cells significantly
increased the length and number of processes. Interestingly, co-expression of motopsin with Sez-6 restrained such effect, although Sez-6 expression showed no effects on the elongation or arborization of processes. Our data indicate the possibility that motopsin modulate neurite elongation with the interaction with Sez-6. Research fund: KAKENHI (20591224). doi:10.1016/j.neures.2011.07.324
O3-G-2-1 Superior haptic-to-visual shape perception in adults with autism psectrum disorders Tamami Nakano 1 , Nobumasa Kato 2 , Shigeru Kitazawa 1 1 2
Dep. of Neurophysiol., Grad. Sch. of Med., Juntendo University, Tokyo, Japan Dep. of Psychiatry, Showa University, Tokyo, Japan
Emerging neurological theories hypothesize that autism disorders result from long-range underconnectivity between distant areas of the brain. This idea led us to hypothesize that haptic shape perception, which involves distributed cortical networks, including motor, somatosensory and parietal cortices, would be impaired in autism spectrum disorders (ASD). Contrary to our expectation, we found that the accuracy in haptic length and orientation discriminations did not differ between adults with and adults without ASD. Moreover, the adults with ASD showed superior performance in haptic-tovisual delayed shape matching compared with adults without ASD, especially for complicated objects. This superiority of haptic-to-visual shape recognition was not explained by an intact visuospatial ability. These results suggested that projections from somatosensory areas to areas that represent shapes in extrinsic coordinates are functionally normal or even enhanced in individuals with ASD. The present findings of superior multimodal processing in ASD argue against the theory of general interregional underconnectivity. Research fund: CREST. doi:10.1016/j.neures.2011.07.325
O3-G-2-2 Multi-dimensional and quantitative scale for PDD and ADHD Yasuko Funabiki , Hisaya Kawagishi, Teruhisa Uwatoko, Sayaka Yoshimura, Kimito Hirose, Toshiya Murai Dept Psychiatry, Med, Kyoto Univ Objective: Inter-individual differences of pervasive developmental disorder (PDD) and attention-deficit/hyperactivity disorder (ADHD) patients are substantial in patterns of symptoms as well as in the severity of each symptom. Therefore, the diagnosis alone is insufficient for grasping the entire clinical profile of these patients or for planning appropriate support for them. We aimed to develop a multi-dimensional comprehensive scale to access daily difficulties applicable both to PDD and ADHD. Methods: We selected 14 domains covering symptoms and difficulties that PDD and ADHD patients often suffer from. Each domain was rated by a nine-point quantitative scale, projected to a radar-chart in which adjacent domains were related. Using this chart, we assessed 179 patients (including autism with mental retardation (MR), autism without MR, Asperger disorder, PDD Not Otherwise Specified (PDDNOS), combined-type ADHD, and inattentive-type ADHD), and then analyzed features by groups. We also estimated the inter-rater reliability within four trained child psychiatrists. Results: This scale can be used easily in clinical practice. The inter-rater reliability was satisfactory. Patients with mild severity are also adequately assessed. Feature analyses showed differences and similarities among the diagnostic groups, although individual differences were also substantial. Conclusions: We have developed a comprehensive multi-dimensional scale to assess daily difficulties in patients with PDD or ADHD. We anticipate that using this scale will improve assessment and therapeutic intervention for these conditions and that it will also contribute to research investigating the biological background of the phenotypic manifestations of these patients. Research fund: Health Labour Science Research Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H21-KokoroWakate-021), Grant-in-Aid for Young Scientists(B)22791122. doi:10.1016/j.neures.2011.07.326
Abstracts / Neuroscience Research 71S (2011) e46–e107
in 1–4% in ASDs. We made the genetically modified mice with a duplication of chromosome 7B-C that is orthologous to human chromosome 15q11–13 using a Cre-loxP mediated chromosome engineering technique. Behavioral battery tests, including 3-chambered social interaction test, reversal learning tasks, and ultrasonic vocalization tests showed mice with paternally inherited duplicated-chromosome (patDp/+) have behavioral abnormalities with poor social interaction, behavioral inflexibility, and developmentally delayed ultrasonic vocalizations that might recapitulate some aspects of autistic symptoms. Previous reports suggest serotonin (5-HT) is the most intriguing neurochemical molecule in ASDs. The 5-HT content in the brains of patDp/+ mice was globally reduced compared with that in wild type mice especially in the postnatal developmental ages. The patDp/+ mouse is regarded as a new model for ASDs because it displays not only behavioral but also genetic similarities with ASDs. Alteration in serotonergic signaling may contribute to autistic like abnormal behaviors. Research fund: JST, CREST. doi:10.1016/j.neures.2011.07.322
O3-G-1-3 Morphological change of dorsal raphe nucleus in rats prenatally exposed to valproic acid: Serotonin neurons in animal models of autism Akiko Oyabu , Takahiro Oyama, Kensaku Ujihara, Michiru Eto, Takeshi Ohkawara, Yasura Tashiro, Masaaki Narita Dept. Dev. and Regenerative Med., Mie Univ., Grad. Sch. of Med., Tsu, Japan The abnormal serotonergic system has been implicated in autism. Although the serotonergic system appears to be developmentally dysregulated in autism, its differentiation during prenatal development is poorly understood. To elucidate the morphogenesis of serotonergic neurons in animal models of autism, we have examined their distributions and axonal tracts in the embryonic hindbrain. Pregnant rats were also exposed to valproic acid (VPA) at embryonic day (E) 9.5, and their embryos at E14.5 and E15.5 were used. The hindbrain was dissected form the embryos, cut along the dorsal midline, opened and whole mounted with ventricular side downwards, which enabled us to observe the whole hindbrain without reconstructing the serial sections. Immunostaining with anti-serotonin antibody showed that the serotonergic neurons were localized to two discrete groups within the hindbrain, medial raphe nucleus (MRN) and dorsal raphe nucleus (DRN). At E14.5, the descending axons from MRN in autism model rats were shorter than those in control. On the other hand, there was no major difference between the descending axons from MRN in models of autism and those in control at E15.5. While DRN neurons in control extended from nearby floor plate to middle of pontine primordium at E14.5, those in animal models of autism located nearby floor plate. In particular, caudal DRN neurons in models of autism maintained to locate nearby floor plate and the abnormal morphology became prominent at E15.5. Thus morphology of serotonergic neurons at E14.5 and E15.5 has already been affected by prenatal VPA exposure. Our findings indicate that disruption of early serotonergic neural development might be involved in the etiology of autism. doi:10.1016/j.neures.2011.07.323
O3-G-1-4 The modulation of neuronal morphology by the interaction between a mental retardation gene, motopsin/neurotrypsin, and seizure related gene (Sez)-6 Shinichi Mitsui , Kazunari Yuri Dept. Neurobiol. & Anat., Kochi Med. Sch., Nankoku, Japan Motopsin is a neuron-specific serine protease, which is composed of a proline-rich domain, a kringle domain, three SRCR domains and a protease domain at the C-terminal. The loss of motopsin function causes severe mental retardation in human and enhances social interaction, but without learning deficit, in mouse. The mosaic structure of motopsin protein suggests that it interacts to other molecules. So we performed an yeast two-hybrid screening against a mouse fetal brain cDNA library and identified Sez-6, which is known to modulate dendritic arborization and synaptogeneis, as a motopsininteracting protein. A two-hybrid analysis and a pulldown assay suggest that the proline-rich and kringle domains of motopsin bind SCR domains of Sez6. When motopsin and Sez-6 were transiently expressed in a neuroblastoma cell lines, neuro2a, both proteins were co-precipitated. Motopsin and Sez-6 were co-localized in primary hippocampal cultured neurons. Immunohistochemical analysis revealed P10 mouse cortical neurons co-expressed both proteins. Further, the expression of motopsin in neuro2a cells significantly
increased the length and number of processes. Interestingly, co-expression of motopsin with Sez-6 restrained such effect, although Sez-6 expression showed no effects on the elongation or arborization of processes. Our data indicate the possibility that motopsin modulate neurite elongation with the interaction with Sez-6. Research fund: KAKENHI (20591224). doi:10.1016/j.neures.2011.07.324
O3-G-2-1 Superior haptic-to-visual shape perception in adults with autism psectrum disorders Tamami Nakano 1 , Nobumasa Kato 2 , Shigeru Kitazawa 1 1 2
Dep. of Neurophysiol., Grad. Sch. of Med., Juntendo University, Tokyo, Japan Dep. of Psychiatry, Showa University, Tokyo, Japan
Emerging neurological theories hypothesize that autism disorders result from long-range underconnectivity between distant areas of the brain. This idea led us to hypothesize that haptic shape perception, which involves distributed cortical networks, including motor, somatosensory and parietal cortices, would be impaired in autism spectrum disorders (ASD). Contrary to our expectation, we found that the accuracy in haptic length and orientation discriminations did not differ between adults with and adults without ASD. Moreover, the adults with ASD showed superior performance in haptic-tovisual delayed shape matching compared with adults without ASD, especially for complicated objects. This superiority of haptic-to-visual shape recognition was not explained by an intact visuospatial ability. These results suggested that projections from somatosensory areas to areas that represent shapes in extrinsic coordinates are functionally normal or even enhanced in individuals with ASD. The present findings of superior multimodal processing in ASD argue against the theory of general interregional underconnectivity. Research fund: CREST. doi:10.1016/j.neures.2011.07.325
O3-G-2-2 Multi-dimensional and quantitative scale for PDD and ADHD Yasuko Funabiki , Hisaya Kawagishi, Teruhisa Uwatoko, Sayaka Yoshimura, Kimito Hirose, Toshiya Murai Dept Psychiatry, Med, Kyoto Univ Objective: Inter-individual differences of pervasive developmental disorder (PDD) and attention-deficit/hyperactivity disorder (ADHD) patients are substantial in patterns of symptoms as well as in the severity of each symptom. Therefore, the diagnosis alone is insufficient for grasping the entire clinical profile of these patients or for planning appropriate support for them. We aimed to develop a multi-dimensional comprehensive scale to access daily difficulties applicable both to PDD and ADHD. Methods: We selected 14 domains covering symptoms and difficulties that PDD and ADHD patients often suffer from. Each domain was rated by a nine-point quantitative scale, projected to a radar-chart in which adjacent domains were related. Using this chart, we assessed 179 patients (including autism with mental retardation (MR), autism without MR, Asperger disorder, PDD Not Otherwise Specified (PDDNOS), combined-type ADHD, and inattentive-type ADHD), and then analyzed features by groups. We also estimated the inter-rater reliability within four trained child psychiatrists. Results: This scale can be used easily in clinical practice. The inter-rater reliability was satisfactory. Patients with mild severity are also adequately assessed. Feature analyses showed differences and similarities among the diagnostic groups, although individual differences were also substantial. Conclusions: We have developed a comprehensive multi-dimensional scale to assess daily difficulties in patients with PDD or ADHD. We anticipate that using this scale will improve assessment and therapeutic intervention for these conditions and that it will also contribute to research investigating the biological background of the phenotypic manifestations of these patients. Research fund: Health Labour Science Research Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H21-KokoroWakate-021), Grant-in-Aid for Young Scientists(B)22791122. doi:10.1016/j.neures.2011.07.326