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Neurodegenerative disease-specific induced pluripotent Stem cells research
S10
Abstracts
SY1-D3-4 Neurodegenerative disease-specific induced pluripotent Stem cells research Haruhisa Inoue 1 , Shiho Kitaoka 1 , Motoko Naitoh 2 , Kazutoshi Takahashi 1 , Katsuhiro Yoshikawa 2 , Satoko Yamawaki 2 , Shigehiko Nakahata 1 , Ryosuke Takahashi 2 , Shinya Suzuki 2 , Tatsutoshi Yamanaka 1 1 Center for iPS Cell Research and Application (CiRA) Institute for integrated Cell-Material Sciences (iCeMS) Kyoto University, Japan; 2 Kyoto University Graduate School of Medicine, Kyoto, Japan
The discovery of induced pluripotent stem (iPS) cells and its technology provide the cell-types affected by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), that is a fatal, yet untreatable neurodegenerative disorder leading to motor neuron degeneration, muscle atrophy, limb paralysis and death. We generated iPS cells from skin fibroblast samples taken from patients with ALS. These disease-specific iPS cells possessed properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS, enabling elucidation of pathogenesis, and effective drug screening. doi:10.1016/j.neures.2009.09.1524
SY1-D3-5 A novel approach to vascular regeneration in subcortical vascular dementia Masafumi Ihara Kyoto University Graduate School of Medicine, Japan Subcortical vascular dementia (SVD) is one of the major subtypes of vascular dementia in elderly people and accounts for at least 10–20% of all dementia cases in developed countries. We have developed a mouse model of chronic cerebral hypoperfusion that is produced by bilateral common carotid artery stenosis using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to damage of the frontal-subcortical circuits (white matter) without apparent gray matter changes, which may serve as a model of subcortical vascular dementia. To explore a novel therapy of this devastating disease, vascular regeneration therapy is applied to this model mouse using iPS cell-derived vascular endothelial cells and a certain vasodilatory peptide. In my presentation, we will introduce our data on new approaches to neurovascular regeneration using our mouse model of SVD. doi:10.1016/j.neures.2009.09.1525
SY1-E1-1 Synaptic development of thalamic lemniscal synapse Mariko Miyata Dept Physiol. Tokyo Wemen’s Med. University, Japan The lemniscal pathway, which conveys tactile information from whiskers on the rodent snout to somatosensory cortex, represents whisker-specific maps in the Pr5 (barrelette), VPm (barreloid), and layer 4 of the barrel cortex. The barreloid map is already formed by P0. However, lemniscal synapses, the primary sensory synapse from Pr5 to VPm, are still immature at this stage. Lemniscal fibers display postnatal synaptic elimination during development, following a time course that is different from the formation of the barreloid map. During the first postnatal 10 days, the number of lemniscal fibers that governs a thalamic relay cell increases gradually. In addition, about 25% of these fibers are silent synapses. NMDA- and AMPAR-mediated EPSCs also grow dramatically at this stage. From P10 to P21, the redundant lemniscal fibers are eliminated and most of relay cells are innervated by one or two lemniscal fibers. During this period, lemniscal synapses begin to show large AMPAR-mediated EPSCs with shorter decay time. After P21, all developmental parameters are stable, thereby indicating that lemniscus synapses are matured by this time. doi:10.1016/j.neures.2009.09.1526
SY1-E1-2 Activity-dependent development of microcircuits in visual cortex Yumiko Yoshimura Okazaki Inst. Integrative Biosci., Japan We showed previously that pairs of layer 2/3 pyramidal cells in visual cortex frequently shared common inputs from nearby excitatory cells in layer 2/3 and 4, when they were monosynaptically connected, suggesting that microcircuits composed of selectively interconnected cells are present within the cortex. In this study using visual cortical slices from normal and dark-reared rats, I tested whether the formation of the microcircuits requires visual experience during development. To this end, I conducted dual whole-cell recordings from layer 2/3 pyramidal cells and cross-correlation analyses of excitatory postsynaptic currents evoked by photo-
stimulation. The detection probability of connections in recorded pairs was lower in dark-reared than in normal rats. In dark-reared rats, pairs of layer 2/3 pyramidal cells rarely shared common inputs from cells in layer 4 and 2/3, regardless of whether they were monosynaptically connected. Thus, the development of microcircuits requires visual experience like the maturation of visual responsiveness of cortical cells, suggesting that the microcircuit is the basis of selective visual responsiveness of neurons. doi:10.1016/j.neures.2009.09.1527
SY1-E1-3 Experience-driven axon reorganization in the visual system Yoshio Hata Div Integrative Biosci, Tottori Univ Grad Sch Med Sci, Yonago, Japan Monocular deprivation in early postnatal life causes a retraction of input axons serving a deprived eye. On the other hand, the afferents serving an open eye selectively retract when cortical neurons are inhibited with a GABA receptor agonist, muscimol, suggesting a presynaptic role in the retraction of input axons in the inhibited cortex. Because muscimol suppresses cortical activity leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of axons. To test this possibility, we inactivated the visual cortex with botulinum neurotoxin type E, which blocks transmitter release, and examined the input axon morphology. Axons in the animals with normal vision showed a significant retraction as observed in the muscimol-treated cortex, whereas those in the binocularly deprived animals were preserved. Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons. doi:10.1016/j.neures.2009.09.1528
SY1-E1-4 Functional Development of Retinotopic Maps Jianhua Cang Northwestern University, USA Neuronal connections are often organized in a spatially precise manner to maintain the nearest neighbor relationships from an origin structure to its target, an arrangement called topographic mapping. A prominent model for studying how topographic maps are established during mammalian development is the projection of retinal ganglion cells to the superior colliculus. We have recently studied the roles of the molecular guidance cues ephrins and structured activity in the development of retinocollicular maps. By studying the overall structure of the retinotopic maps with intrinsic signal imaging andcomparing the experimental data with a computational model, we have revealed the contributions of ephrin-As and activity-dependent mechanisms in retinocollicular map formation. These studies also provide a unique opportunity for studying the role of the retinotopic map, an orderly physical layout, in the physiological processing of sensory information. doi:10.1016/j.neures.2009.09.1529
SY1-E1-5 Neural circuit and map formation in the mouse olfactory system Hitoshi Sakano Dept Biophys & Biochem, Grad Sch Sci, Univ of Tokyo, Tokyo, Japan In mammals, olfactory sensory neurons (OSNs) expressing a given odorant receptor (OR) converge their axons to a specific pair of glomeruli in the olfactory bulb (OB). It is generally accepted that the topography of a neural map is shaped by target-derived guidance cues, so-called the chemoaffinity model. However, our recent study demonstrated that axon–axon interactions in the bundle play important roles in glomerular map formation in the mouse. It was found that Neuropilin-1 and its repulsive ligand Sema-3A mediate axonal projection of OSNs along the anterior-posterior axis. OSN-specific knockout of Neuropilin-1 or Sema-3A perturbs the axonal organization within the bundle and alters the glomerular map topography. It was also found that Neuropilin-2 and its repulsive ligand Sema-3F are expressed in OSNs in a complementary manner and involved in the glomerular positioning along the dorsal-ventral axis. In the Neuropilin-2 or Sema-3F knockout, dorsal shift of glomeruli was found for some OR species. These results indicate that pre-target axonal interactions are essential for the topographic map formation in the brain. doi:10.1016/j.neures.2009.09.1530
Abstracts
SY1-D3-4 Neurodegenerative disease-specific induced pluripotent Stem cells research Haruhisa Inoue 1 , Shiho Kitaoka 1 , Motoko Naitoh 2 , Kazutoshi Takahashi 1 , Katsuhiro Yoshikawa 2 , Satoko Yamawaki 2 , Shigehiko Nakahata 1 , Ryosuke Takahashi 2 , Shinya Suzuki 2 , Tatsutoshi Yamanaka 1 1 Center for iPS Cell Research and Application (CiRA) Institute for integrated Cell-Material Sciences (iCeMS) Kyoto University, Japan; 2 Kyoto University Graduate School of Medicine, Kyoto, Japan
The discovery of induced pluripotent stem (iPS) cells and its technology provide the cell-types affected by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), that is a fatal, yet untreatable neurodegenerative disorder leading to motor neuron degeneration, muscle atrophy, limb paralysis and death. We generated iPS cells from skin fibroblast samples taken from patients with ALS. These disease-specific iPS cells possessed properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS, enabling elucidation of pathogenesis, and effective drug screening. doi:10.1016/j.neures.2009.09.1524
SY1-D3-5 A novel approach to vascular regeneration in subcortical vascular dementia Masafumi Ihara Kyoto University Graduate School of Medicine, Japan Subcortical vascular dementia (SVD) is one of the major subtypes of vascular dementia in elderly people and accounts for at least 10–20% of all dementia cases in developed countries. We have developed a mouse model of chronic cerebral hypoperfusion that is produced by bilateral common carotid artery stenosis using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to damage of the frontal-subcortical circuits (white matter) without apparent gray matter changes, which may serve as a model of subcortical vascular dementia. To explore a novel therapy of this devastating disease, vascular regeneration therapy is applied to this model mouse using iPS cell-derived vascular endothelial cells and a certain vasodilatory peptide. In my presentation, we will introduce our data on new approaches to neurovascular regeneration using our mouse model of SVD. doi:10.1016/j.neures.2009.09.1525
SY1-E1-1 Synaptic development of thalamic lemniscal synapse Mariko Miyata Dept Physiol. Tokyo Wemen’s Med. University, Japan The lemniscal pathway, which conveys tactile information from whiskers on the rodent snout to somatosensory cortex, represents whisker-specific maps in the Pr5 (barrelette), VPm (barreloid), and layer 4 of the barrel cortex. The barreloid map is already formed by P0. However, lemniscal synapses, the primary sensory synapse from Pr5 to VPm, are still immature at this stage. Lemniscal fibers display postnatal synaptic elimination during development, following a time course that is different from the formation of the barreloid map. During the first postnatal 10 days, the number of lemniscal fibers that governs a thalamic relay cell increases gradually. In addition, about 25% of these fibers are silent synapses. NMDA- and AMPAR-mediated EPSCs also grow dramatically at this stage. From P10 to P21, the redundant lemniscal fibers are eliminated and most of relay cells are innervated by one or two lemniscal fibers. During this period, lemniscal synapses begin to show large AMPAR-mediated EPSCs with shorter decay time. After P21, all developmental parameters are stable, thereby indicating that lemniscus synapses are matured by this time. doi:10.1016/j.neures.2009.09.1526
SY1-E1-2 Activity-dependent development of microcircuits in visual cortex Yumiko Yoshimura Okazaki Inst. Integrative Biosci., Japan We showed previously that pairs of layer 2/3 pyramidal cells in visual cortex frequently shared common inputs from nearby excitatory cells in layer 2/3 and 4, when they were monosynaptically connected, suggesting that microcircuits composed of selectively interconnected cells are present within the cortex. In this study using visual cortical slices from normal and dark-reared rats, I tested whether the formation of the microcircuits requires visual experience during development. To this end, I conducted dual whole-cell recordings from layer 2/3 pyramidal cells and cross-correlation analyses of excitatory postsynaptic currents evoked by photo-
stimulation. The detection probability of connections in recorded pairs was lower in dark-reared than in normal rats. In dark-reared rats, pairs of layer 2/3 pyramidal cells rarely shared common inputs from cells in layer 4 and 2/3, regardless of whether they were monosynaptically connected. Thus, the development of microcircuits requires visual experience like the maturation of visual responsiveness of cortical cells, suggesting that the microcircuit is the basis of selective visual responsiveness of neurons. doi:10.1016/j.neures.2009.09.1527
SY1-E1-3 Experience-driven axon reorganization in the visual system Yoshio Hata Div Integrative Biosci, Tottori Univ Grad Sch Med Sci, Yonago, Japan Monocular deprivation in early postnatal life causes a retraction of input axons serving a deprived eye. On the other hand, the afferents serving an open eye selectively retract when cortical neurons are inhibited with a GABA receptor agonist, muscimol, suggesting a presynaptic role in the retraction of input axons in the inhibited cortex. Because muscimol suppresses cortical activity leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of axons. To test this possibility, we inactivated the visual cortex with botulinum neurotoxin type E, which blocks transmitter release, and examined the input axon morphology. Axons in the animals with normal vision showed a significant retraction as observed in the muscimol-treated cortex, whereas those in the binocularly deprived animals were preserved. Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons. doi:10.1016/j.neures.2009.09.1528
SY1-E1-4 Functional Development of Retinotopic Maps Jianhua Cang Northwestern University, USA Neuronal connections are often organized in a spatially precise manner to maintain the nearest neighbor relationships from an origin structure to its target, an arrangement called topographic mapping. A prominent model for studying how topographic maps are established during mammalian development is the projection of retinal ganglion cells to the superior colliculus. We have recently studied the roles of the molecular guidance cues ephrins and structured activity in the development of retinocollicular maps. By studying the overall structure of the retinotopic maps with intrinsic signal imaging andcomparing the experimental data with a computational model, we have revealed the contributions of ephrin-As and activity-dependent mechanisms in retinocollicular map formation. These studies also provide a unique opportunity for studying the role of the retinotopic map, an orderly physical layout, in the physiological processing of sensory information. doi:10.1016/j.neures.2009.09.1529
SY1-E1-5 Neural circuit and map formation in the mouse olfactory system Hitoshi Sakano Dept Biophys & Biochem, Grad Sch Sci, Univ of Tokyo, Tokyo, Japan In mammals, olfactory sensory neurons (OSNs) expressing a given odorant receptor (OR) converge their axons to a specific pair of glomeruli in the olfactory bulb (OB). It is generally accepted that the topography of a neural map is shaped by target-derived guidance cues, so-called the chemoaffinity model. However, our recent study demonstrated that axon–axon interactions in the bundle play important roles in glomerular map formation in the mouse. It was found that Neuropilin-1 and its repulsive ligand Sema-3A mediate axonal projection of OSNs along the anterior-posterior axis. OSN-specific knockout of Neuropilin-1 or Sema-3A perturbs the axonal organization within the bundle and alters the glomerular map topography. It was also found that Neuropilin-2 and its repulsive ligand Sema-3F are expressed in OSNs in a complementary manner and involved in the glomerular positioning along the dorsal-ventral axis. In the Neuropilin-2 or Sema-3F knockout, dorsal shift of glomeruli was found for some OR species. These results indicate that pre-target axonal interactions are essential for the topographic map formation in the brain. doi:10.1016/j.neures.2009.09.1530