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Novel ataxia mouse with heavy neuropathological changes in the dorsal root ganglion neurons
Abstracts / Neuroscience Research 68S (2010) e335–e446
P3-p25 Novel ataxia mouse with heavy neuropathological changes in the dorsal root ganglion neurons Moriaki Kusakabe 1,2,3 , Toshiaki Tachibana 4 , Miki Tanzawa 5 , Tomonori Kawabe 5 , Jorge E. Zavaleta-Ahane 5 , Takahiro Fukuda 6 , Hisashi Hashimoto 4 1 Res. Ctr. of Food Safety, Grad. Sch. of Agricul. and Life Sci., University of Tokyo, Tokyo, Japan 2 Exp. Anim. Res. Ctr., Inst. for Anim. Rep., Kasumigaura, Japan 3 Matrix Cell Res. Inst., Inc., Ushiku, Japan 4 Department Anat., Jikei. University Sch. Med., Tokyo, Japan 5 Tokyo Col. Medico-Pharmaco Tech., Tokyo, Japan 6 Department Neuropath, Jikei. University Sch. Med., Tokyo, Japan
We have investigated the neuropathological changes in the peripheral nervous system of a novel ataxia mouse that presents with severe gait disorder of the hind legs. On the transverse sections of the lumbar spinal nerves, many vacuoles were present within nerve fibers. Longitudinal sections revealed swelling and vacuoles in both the spinal nerve and the radix. In the lumbar dorsal root ganglion, some of the perikaryon of the larger neuron showed autolysis, while that of the smaller neuron looked intact. The shape of the lysed neuron, however, was preserved and some satellite cells encircled the neuron. No inflammatory cell infiltration was observed. The autolysis of the larger neuron was also found in the cervical and thoracic dorsal root ganglia. These results suggest that gait disorder of the hind legs is caused by neuropathy of the proprioception.
e431
dramatically-decreased expressions of GABAergic interneurons in the anterior cingulate and somatosensory cortices. To explore the possibility that the increased anxiety is caused by abnormalities in cortical inhibitory neural function, we investigated the kinetics of high frequency cortical activity on spontaneous anxiety of bv mice and cholecystokinin (CCK)-induced anxiety. In bv (n = 5) and control mice (n = 5) at 3 to 6 months of age, stainless steel screw electrode for EEG recording was placed epidurally on the left parietal cortex. For multi-unit recordings, the tip of stainless steel wire electrode was located within the right cingulate cortex. After recovery, wide band cortical EEG and multi-unit activity were recorded from the freely-moving mice in an acrylic experimental box. The wide band EEG data was filtered with bandpass filter 80-500 Hz to cover oscillation in high gamma, ripple and fast ripple frequency. Power spectrum analysis of these frequency bands was performed by using fast Fourier transform. Averaged spectral power pattern showed that bv mice have remarkably lower power than control mice in the 80–500 Hz frequency band. In addition, control mice which received intraperitoneal administration of 30 g/kg CCK, also showed reduced EEG power in this frequency range compared with that of pre-administration. Spontaneous multi-unit neuronal activity was lower in bv mouse relative to control. CCK administration produced a transient decrease of the multiunit activity in controls. These results suggest a possibility that pathological anxiety states include the reduced activity of high frequency component in parietal cortex, reflecting the inhibitory interneuron activity. doi:10.1016/j.neures.2010.07.1911
doi:10.1016/j.neures.2010.07.1909
P3-p26 VLDLR overexpression rat: Evaluation as an animal model of autism Keiko Iwata 1 , Hideo Matsuzaki 1 , Nobuo Izumo 2 , Yukio Ichitani 3 , Norio Mori 4
1 Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine 2 Department of Clinical Pharmacy, Yokohama College of Pharmacy 3 Institute of Psychology and Behavioral Neuroscience, University of Tsukuba 4 Department of Psychiatry and Neurology, Hamamatsu University School of Medicine
Autism is a neurodevelopmental disorder characterized by severe and sustained impairment in social interaction, deviance in communication, and patterns of behavior and interest that are restricted or stereotyped. It is believed that autism results from a neurological defect that impairs the brain’s capacity to organize and interpret perceptual stimuli in a meaningful way, but neurobiological basis for autism remains poorly understood. It has been reported that approximately 50% of individuals with Smith-Lemli-Opitz syndrome, a genetic condition of impaired cholesterol biosynthesis, met the criteria for autism (Bukelis et al., 2007). Therefore, we focused on lipid metabolism, and analyzed peripheral lipid profiles by using blood of individuals with high-functioning autism. We found that the serum levels of VLDL cholesterol and triglyceride in the subjects with high-functioning autism were significantly lower than those of normal control subjects, respectively. Moreover, it has been reported that level of VLDL receptor (VLDLR) mRNA was increased in post mortem studies of autistic brain (Fatemi et al., 2005). These suggest that molecules which participate in metabolism of VLDL might be implicated in the pathophysiology of high-functioning autism. Based on these findings, we generated VLDLR-transgenic (Tg) rats and examined if its biological and behavioral features are appropriate as novel animal model of autism. We found that the spontaneous locomotor activities in Tg rats were significantly increased. In contrast, Tg rats did not show testing performance deficits in radial maze, suggesting that spatial memory is intact. These results suggest that VLDLR level might be involved in behavioral abnormalities, at least hyperactivity. We will also investigate ultrasonic vocalizations to address communication deficit. doi:10.1016/j.neures.2010.07.1910
P3-p27 Electrophysiological analysis of high frequency cortical activity related with anxiety state of mice Yoshiki Matsuda 1 , Hitomi Izumi 1 , Yuki Inoue 1 , Makiko Kaga 1 , Masumi Inagaki 1 , Yu-ichi Goto 2 1
Natl. Inst. Ment. Health, NCNP, Tokyo, Japan 2 Natl. Inst. Neurosci., NCNP, Tokyo, Japan The homozygous Bronx waltzer (bv) mouse is known as a model of congenital hearing and vestibular dysfunction. We have already confirmed that bv mice present with an increased anxiety in the elevated plus maze paradigm and
P3-p28 Development of mutant NOTCH3 knock-in mice as a model for CADASIL
Shohko Kunimoto 1 , Atsushi Watanabe 1 , Kayo Adachi 1 , Mikiko Matsuzaki 1 , Kazuya Takeda 1 , Hideaki Wakita 1 , Rajesh N. 2 1 Kalaria , Wakako Maruyama , Keikichi Takahashi 1 1
NCGG, Aichi, Japan 2 Newcastle Univ, Newcastle upon Tyne, UK
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common hereditary small vessel disease that is characterized by recurrent subcortical ischemic strokes and ultimately vascular dementia. It is linked to dominant mutations in the human NOTCH3 gene, which encodes a transmembrane receptor and is primarily expressed in vascular smooth muscle cells (VSMCs) of the vessel wall. Pathological features of CADASIL are degeneration and loss of VSMCs and abnormal accumulation of granular osmiophilic material (GOM) that is associated with the extracellular domain of Notch3, yet the pathogenic mechanisms remain unclear by the lack of a good animal model. Here, we generated a knock-in mouse model for one of the CADASIL mutations, a cysteine to tyrosine transition at position 224, C224Y, which corresponds to mutation C225Y in mouse NOTCH3. Sequence analysis of cDNA clones from the KI mouse confirmed the expression of NOTCH3 from the mutated allele. We investigated this mouse to elucidate whether the pathological hallmarks of CADASIL are observed with mutant Notch3: reduction in alpha-smooth muscle actin in VSMCs, thickening of the vessel wall by increased collagen type IV, accumulation of Notch3 protein. Further, we examined the effect of chronic intermittent restraint stress (CIRS) on the pathogenesis of CADASIL using KI mice and wild-type mice. We hypothesize that, in individuals predisposed to genetic mutations for CADASIL, a mutated gene-environmental stress interaction could synergistically accelerate the onset of CADASIL phenotype. Our experimental strategy using the KI mouse line with controlled stress could provide an animal model for analyses of the pathogenic mechanisms of CADASIL as well as the more common forms of ischaemic cerebral small-artery diseases and subcortical ischaemic vascular dementia. doi:10.1016/j.neures.2010.07.1912
P3-q01 Proteomics analysis of new animal models of bipolar disorder Hiroshi Ageta 1 , Kaoru Inokuchi 2 , Kunihiro Tsuchida 1 1 2
Institute for comprehensive medical science, Fujita Health University University of Toyama, Toyama, Japan
Activin A, wich is know as a member of the TGF beta superfamily, regulates various biological functions including development and differentiation of numerous cell types. We previously generated activin and follistatin (an activin inhibitor) transgenic mice under the control of CaMKII promoter. Follistatin over-expression mice showed decrease in general locomotor activity and enhanced anxiety. By contrast, activin over-expression mice showed more aggressive behavior than the wild type littermates and reduced
P3-p25 Novel ataxia mouse with heavy neuropathological changes in the dorsal root ganglion neurons Moriaki Kusakabe 1,2,3 , Toshiaki Tachibana 4 , Miki Tanzawa 5 , Tomonori Kawabe 5 , Jorge E. Zavaleta-Ahane 5 , Takahiro Fukuda 6 , Hisashi Hashimoto 4 1 Res. Ctr. of Food Safety, Grad. Sch. of Agricul. and Life Sci., University of Tokyo, Tokyo, Japan 2 Exp. Anim. Res. Ctr., Inst. for Anim. Rep., Kasumigaura, Japan 3 Matrix Cell Res. Inst., Inc., Ushiku, Japan 4 Department Anat., Jikei. University Sch. Med., Tokyo, Japan 5 Tokyo Col. Medico-Pharmaco Tech., Tokyo, Japan 6 Department Neuropath, Jikei. University Sch. Med., Tokyo, Japan
We have investigated the neuropathological changes in the peripheral nervous system of a novel ataxia mouse that presents with severe gait disorder of the hind legs. On the transverse sections of the lumbar spinal nerves, many vacuoles were present within nerve fibers. Longitudinal sections revealed swelling and vacuoles in both the spinal nerve and the radix. In the lumbar dorsal root ganglion, some of the perikaryon of the larger neuron showed autolysis, while that of the smaller neuron looked intact. The shape of the lysed neuron, however, was preserved and some satellite cells encircled the neuron. No inflammatory cell infiltration was observed. The autolysis of the larger neuron was also found in the cervical and thoracic dorsal root ganglia. These results suggest that gait disorder of the hind legs is caused by neuropathy of the proprioception.
e431
dramatically-decreased expressions of GABAergic interneurons in the anterior cingulate and somatosensory cortices. To explore the possibility that the increased anxiety is caused by abnormalities in cortical inhibitory neural function, we investigated the kinetics of high frequency cortical activity on spontaneous anxiety of bv mice and cholecystokinin (CCK)-induced anxiety. In bv (n = 5) and control mice (n = 5) at 3 to 6 months of age, stainless steel screw electrode for EEG recording was placed epidurally on the left parietal cortex. For multi-unit recordings, the tip of stainless steel wire electrode was located within the right cingulate cortex. After recovery, wide band cortical EEG and multi-unit activity were recorded from the freely-moving mice in an acrylic experimental box. The wide band EEG data was filtered with bandpass filter 80-500 Hz to cover oscillation in high gamma, ripple and fast ripple frequency. Power spectrum analysis of these frequency bands was performed by using fast Fourier transform. Averaged spectral power pattern showed that bv mice have remarkably lower power than control mice in the 80–500 Hz frequency band. In addition, control mice which received intraperitoneal administration of 30 g/kg CCK, also showed reduced EEG power in this frequency range compared with that of pre-administration. Spontaneous multi-unit neuronal activity was lower in bv mouse relative to control. CCK administration produced a transient decrease of the multiunit activity in controls. These results suggest a possibility that pathological anxiety states include the reduced activity of high frequency component in parietal cortex, reflecting the inhibitory interneuron activity. doi:10.1016/j.neures.2010.07.1911
doi:10.1016/j.neures.2010.07.1909
P3-p26 VLDLR overexpression rat: Evaluation as an animal model of autism Keiko Iwata 1 , Hideo Matsuzaki 1 , Nobuo Izumo 2 , Yukio Ichitani 3 , Norio Mori 4
1 Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine 2 Department of Clinical Pharmacy, Yokohama College of Pharmacy 3 Institute of Psychology and Behavioral Neuroscience, University of Tsukuba 4 Department of Psychiatry and Neurology, Hamamatsu University School of Medicine
Autism is a neurodevelopmental disorder characterized by severe and sustained impairment in social interaction, deviance in communication, and patterns of behavior and interest that are restricted or stereotyped. It is believed that autism results from a neurological defect that impairs the brain’s capacity to organize and interpret perceptual stimuli in a meaningful way, but neurobiological basis for autism remains poorly understood. It has been reported that approximately 50% of individuals with Smith-Lemli-Opitz syndrome, a genetic condition of impaired cholesterol biosynthesis, met the criteria for autism (Bukelis et al., 2007). Therefore, we focused on lipid metabolism, and analyzed peripheral lipid profiles by using blood of individuals with high-functioning autism. We found that the serum levels of VLDL cholesterol and triglyceride in the subjects with high-functioning autism were significantly lower than those of normal control subjects, respectively. Moreover, it has been reported that level of VLDL receptor (VLDLR) mRNA was increased in post mortem studies of autistic brain (Fatemi et al., 2005). These suggest that molecules which participate in metabolism of VLDL might be implicated in the pathophysiology of high-functioning autism. Based on these findings, we generated VLDLR-transgenic (Tg) rats and examined if its biological and behavioral features are appropriate as novel animal model of autism. We found that the spontaneous locomotor activities in Tg rats were significantly increased. In contrast, Tg rats did not show testing performance deficits in radial maze, suggesting that spatial memory is intact. These results suggest that VLDLR level might be involved in behavioral abnormalities, at least hyperactivity. We will also investigate ultrasonic vocalizations to address communication deficit. doi:10.1016/j.neures.2010.07.1910
P3-p27 Electrophysiological analysis of high frequency cortical activity related with anxiety state of mice Yoshiki Matsuda 1 , Hitomi Izumi 1 , Yuki Inoue 1 , Makiko Kaga 1 , Masumi Inagaki 1 , Yu-ichi Goto 2 1
Natl. Inst. Ment. Health, NCNP, Tokyo, Japan 2 Natl. Inst. Neurosci., NCNP, Tokyo, Japan The homozygous Bronx waltzer (bv) mouse is known as a model of congenital hearing and vestibular dysfunction. We have already confirmed that bv mice present with an increased anxiety in the elevated plus maze paradigm and
P3-p28 Development of mutant NOTCH3 knock-in mice as a model for CADASIL
Shohko Kunimoto 1 , Atsushi Watanabe 1 , Kayo Adachi 1 , Mikiko Matsuzaki 1 , Kazuya Takeda 1 , Hideaki Wakita 1 , Rajesh N. 2 1 Kalaria , Wakako Maruyama , Keikichi Takahashi 1 1
NCGG, Aichi, Japan 2 Newcastle Univ, Newcastle upon Tyne, UK
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common hereditary small vessel disease that is characterized by recurrent subcortical ischemic strokes and ultimately vascular dementia. It is linked to dominant mutations in the human NOTCH3 gene, which encodes a transmembrane receptor and is primarily expressed in vascular smooth muscle cells (VSMCs) of the vessel wall. Pathological features of CADASIL are degeneration and loss of VSMCs and abnormal accumulation of granular osmiophilic material (GOM) that is associated with the extracellular domain of Notch3, yet the pathogenic mechanisms remain unclear by the lack of a good animal model. Here, we generated a knock-in mouse model for one of the CADASIL mutations, a cysteine to tyrosine transition at position 224, C224Y, which corresponds to mutation C225Y in mouse NOTCH3. Sequence analysis of cDNA clones from the KI mouse confirmed the expression of NOTCH3 from the mutated allele. We investigated this mouse to elucidate whether the pathological hallmarks of CADASIL are observed with mutant Notch3: reduction in alpha-smooth muscle actin in VSMCs, thickening of the vessel wall by increased collagen type IV, accumulation of Notch3 protein. Further, we examined the effect of chronic intermittent restraint stress (CIRS) on the pathogenesis of CADASIL using KI mice and wild-type mice. We hypothesize that, in individuals predisposed to genetic mutations for CADASIL, a mutated gene-environmental stress interaction could synergistically accelerate the onset of CADASIL phenotype. Our experimental strategy using the KI mouse line with controlled stress could provide an animal model for analyses of the pathogenic mechanisms of CADASIL as well as the more common forms of ischaemic cerebral small-artery diseases and subcortical ischaemic vascular dementia. doi:10.1016/j.neures.2010.07.1912
P3-q01 Proteomics analysis of new animal models of bipolar disorder Hiroshi Ageta 1 , Kaoru Inokuchi 2 , Kunihiro Tsuchida 1 1 2
Institute for comprehensive medical science, Fujita Health University University of Toyama, Toyama, Japan
Activin A, wich is know as a member of the TGF beta superfamily, regulates various biological functions including development and differentiation of numerous cell types. We previously generated activin and follistatin (an activin inhibitor) transgenic mice under the control of CaMKII promoter. Follistatin over-expression mice showed decrease in general locomotor activity and enhanced anxiety. By contrast, activin over-expression mice showed more aggressive behavior than the wild type littermates and reduced