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Perinatal BPA exposure impairs synaptic architectures and functions in the hippocampus of offspring
Abstracts / Neuroscience Research 58S (2007) S1–S244
P3-j3Ø Behavioral and histological examinations in TR-alpha or TR-beta deficient mice Sadamatsu 1 ,
Kanai 2 ,
Kato 3
Miyuki Hirohiko Nobumasa Department of Psychiatry, Nara Medical University, Kashihara, Japan; 2 Department of Psychiatry, Shiga University Medical Science, Otsu, Japan; 3 Department of Psychiatry, Faculty of Medicine, Showa University, Tokyo, Japan
1
Thyroid functions are well known to participate in neuronal development after birth in mice. The drug-induced hypothyroidism in a early period of the neuronal development results in permanent behavioral abnormality, including memory disturbance and hyperactivity. However, the relevance of the memory disturbance and the hyperactivity to thyroid hormone receptors, TR-alpha and TR-beta, remains unknown. To address this issue, we performed histological examination and behavioral experiments, including open field and radial maze in TR-alpha and TR-beta deficient mice. In open field experiment, the TR-alpha deficient mice exhibited the tendency of hyperactivity, but unexpectedly we did not observed any gross behavioral abnormalities in TR-beta deficient mice. In this study, we explored the possible involvement of the thyroid hormone signaling in the development of the brain functions after birth.
S239
P3-j34 Brain proteins with PDZ domains associated with RA175/SynCAM Yuko Tanabe 1 , Ayumi Matsuzaki 1 , Eriko Fujita 1 , Giulo Piluso 2 , Shigeo Ohno 3 , Shouichi Ishiura 4 , Alaa Hussein 5 , Vencenzo Nigro 2 , Takashi Momoi 1 1 National Institute of Neuroscience,Tokyo, Japan; 2 Seconda University, Napoli, Italy; 3 Yokohama City University Graduate School of Medical Science; 4 University, Tokyo; 5 University British Columbia, Vancouver, BC, Canada Association of neuroligins with PSD-95 and Shank controls the balance between neuronal excitation and inhibition. Mutations of neuroligin-3 and Shank-3 have been detected in the patient of Autism. RA175/SynCAM, homophilic cell adhesion molecule with PDZ binding domain at Cterminal, is also involved in the formation of functional synapse. RA175/SynCAM interacts with CASK at presynapse, but little is known about the binding molecules at postsynapse. We examined the RA175Cterminal binding protein in mouse brain by yeast two hybrid analysis and pull-down assay. Unlike neuroligin, RA175 directly band with Par-3 and RA175 had a complex with Shank but not with PSD-95. RA175 may be associated with Shank via other scaffolding molecules with PDZ domain. We will discuss this putative complex associated with the autism. Research funds: KAKENHI (18700333), Research for Nervous and Mental Disorders (17A-1).
P3-j32 CtBPs are binding proteins of the novel isoform of FoxP2 lacking forkhead domain Eriko Fujita 1 , Ayumi Matsuzaki 1,2 , Yuko Tanabe 1 , Tadashi Kasahara 2 , Mariko Momoi 3 , Takashi Momoi 1 1 National Institute of Neuroscience, NCNP, Japan; 2 Kyoritsu University of Pharmacy, Tokyo, Japan; 3 Jichi Medical University, Tochigi, Japan The mutations of FOXP2 have been detected in the family of the speech/language disorder. Recently, we identified the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. In contrast with wildtype, the mutated FOXP2s are located in the cytoplasm. However, we also identified the novel isofrom lacking forkhead domain located in the cytoplasm of Perkinje cells (P2-P10). To examine the biological role of the novel isoform, we tried to isolate the proteins binding with the novel isoform of FOXP2 by yeast-two-hybrid system. Here we show that this isoform specifically binds with CtBPs with multifuctions such as repressor, golgi fission, and synapticvesicle fusion. The novel isoform may be involved in the synaptic function via binding with CtBPs. Research fund: KAKENHI (18700333).
P3-j33 Identification of a novel isoform of Foxp2 located in the cytoplasm of mouse developing Purkinje cells Ayumi Matsuzaki 1,2 , Yuko Tanabe 1 , Eriko Fujita 1 , Tadashi Kasahara 2 , Takashi Momoi 1 1 Department of Inherited Metabolic Diseases, NCNP, Tokyo, Japan; 2 Department of Biochemistry, Kyoritsu University of Pharmacy, Tokyo, Japan FOXP2 belongs to a newly identified subfamily of Forkhead box (FOX)transcription factors. The mutations of FOXP2 have been detected in the family of the speech/language disorder, suggesting that FOXP2 is involved in acquiring human speech/language ability. In contrast with wild type, the mutated FOXP2s are located in the cytoplasm. In the present study, we identified the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depends on two distally separated nuclear localization signals in the forkhead domain. Furthermore, we identified the novel isofrom lacking forkhead domain located in the cytoplasm during mouse brain development. In the mouse cerebellum, this novel isoform was mainly detected in the cytoplasm of the Purkinje cells (P2-P10), but not in those of P15-P22. This novel isoform may be involved in the acquiring mouse “singing” ability related to the human speech/language ability.
P3-j35 Perinatal BPA exposure impairs synaptic architectures and functions in the hippocampus of offspring Ling Chen 1 , Masahiro Sokabe 2,3 Dept Physiol, Nanjing Med Univ, Nanjing, China; 2 Dept Physiol, Nagoya Univ Grad Sch Med, Nagoya, Japan; 3 ICORP/SORST Cell Mechanosensing, JST, Nagoya, Japan
1
Humans are routinely exposed to the environmental estrogen bisphenol A (BPA) leaking from food and beverage containers. Exposure to low doses of BPA are known to affect a variety of animal behaviors including memory and learning. Here we report that perinatal exposure to a low dose of BPA (100 ng/kg) impaired the maze learning, and increased the spontaneous motor activities of 4 weeks male offspring. We investigated the neuronal functions and ultra-structures of the hippocampal CA1 region in these animals. Basal synaptic transmission and population spikes were significantly enhanced, whereas tetanic LTP was impaired without changes in the paired-pulse facilitation. Although the density and spatial configuration of pyramidal cells looked normal, their spines and synaptic contacts at apical dendrites were morphologically altered. These results suggest that perinatal exposure to BPA will alter the hippocampal synaptic architectures and functions, resulting in behavioral abnormalities of the offspring.
P3-j36 Effects of mitochondrial ATP-sensitive K channel opening during ischemia/reperfusion in neurons Nobuhiro Matsuoka 1 , Shigeyuki Yamada 1 , Masaaki Shizukuisi 1 , Tomiei Kazama 1 , Yasushi Kobayashi 2 , Hideyuki Ishida 3 1 Department of Anesthesiology, National Defense Medical College, Saitama, Japan; 2 Department of Anatomy and Neurobiology, National Defense Medical College, Saitama, Japan; 3 Department of Physiology, Tokai University, Kanagawa, Japan We investigated the effect of mitochondrial ATP-sensitive K (mitoKATP ) channel opening on the ability of oxygen glucose deprivation (OGD) to prevent intracellular Ca2+ ([Ca2+ ]i ) overload or ψm depolarization in rat hippocampal CA1 pyramidal cells. Acute hippocampal slices were preloaded with [Ca2+ ]i indicator or ψm indicator. Simulated ischemia was performed by subjecting to a 10-min OGD, then slices were recovered for 5 min. Relative changes in the [Ca2+ ]i and the ψm were measured by confocal system. After OGD the [Ca2+ ]i increased and the ψm deceased, but both deceased after recovery phase. Ischemic preconditioning (1-min OGD) and anti-anginal drug nicorandil dramatically reduced the [Ca2+ ]i overload and ψm depolarization resulting from OGD. These results suggest that mitoKATP channel opening might be attributed to the mechanism of neuroprotection.
P3-j3Ø Behavioral and histological examinations in TR-alpha or TR-beta deficient mice Sadamatsu 1 ,
Kanai 2 ,
Kato 3
Miyuki Hirohiko Nobumasa Department of Psychiatry, Nara Medical University, Kashihara, Japan; 2 Department of Psychiatry, Shiga University Medical Science, Otsu, Japan; 3 Department of Psychiatry, Faculty of Medicine, Showa University, Tokyo, Japan
1
Thyroid functions are well known to participate in neuronal development after birth in mice. The drug-induced hypothyroidism in a early period of the neuronal development results in permanent behavioral abnormality, including memory disturbance and hyperactivity. However, the relevance of the memory disturbance and the hyperactivity to thyroid hormone receptors, TR-alpha and TR-beta, remains unknown. To address this issue, we performed histological examination and behavioral experiments, including open field and radial maze in TR-alpha and TR-beta deficient mice. In open field experiment, the TR-alpha deficient mice exhibited the tendency of hyperactivity, but unexpectedly we did not observed any gross behavioral abnormalities in TR-beta deficient mice. In this study, we explored the possible involvement of the thyroid hormone signaling in the development of the brain functions after birth.
S239
P3-j34 Brain proteins with PDZ domains associated with RA175/SynCAM Yuko Tanabe 1 , Ayumi Matsuzaki 1 , Eriko Fujita 1 , Giulo Piluso 2 , Shigeo Ohno 3 , Shouichi Ishiura 4 , Alaa Hussein 5 , Vencenzo Nigro 2 , Takashi Momoi 1 1 National Institute of Neuroscience,Tokyo, Japan; 2 Seconda University, Napoli, Italy; 3 Yokohama City University Graduate School of Medical Science; 4 University, Tokyo; 5 University British Columbia, Vancouver, BC, Canada Association of neuroligins with PSD-95 and Shank controls the balance between neuronal excitation and inhibition. Mutations of neuroligin-3 and Shank-3 have been detected in the patient of Autism. RA175/SynCAM, homophilic cell adhesion molecule with PDZ binding domain at Cterminal, is also involved in the formation of functional synapse. RA175/SynCAM interacts with CASK at presynapse, but little is known about the binding molecules at postsynapse. We examined the RA175Cterminal binding protein in mouse brain by yeast two hybrid analysis and pull-down assay. Unlike neuroligin, RA175 directly band with Par-3 and RA175 had a complex with Shank but not with PSD-95. RA175 may be associated with Shank via other scaffolding molecules with PDZ domain. We will discuss this putative complex associated with the autism. Research funds: KAKENHI (18700333), Research for Nervous and Mental Disorders (17A-1).
P3-j32 CtBPs are binding proteins of the novel isoform of FoxP2 lacking forkhead domain Eriko Fujita 1 , Ayumi Matsuzaki 1,2 , Yuko Tanabe 1 , Tadashi Kasahara 2 , Mariko Momoi 3 , Takashi Momoi 1 1 National Institute of Neuroscience, NCNP, Japan; 2 Kyoritsu University of Pharmacy, Tokyo, Japan; 3 Jichi Medical University, Tochigi, Japan The mutations of FOXP2 have been detected in the family of the speech/language disorder. Recently, we identified the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. In contrast with wildtype, the mutated FOXP2s are located in the cytoplasm. However, we also identified the novel isofrom lacking forkhead domain located in the cytoplasm of Perkinje cells (P2-P10). To examine the biological role of the novel isoform, we tried to isolate the proteins binding with the novel isoform of FOXP2 by yeast-two-hybrid system. Here we show that this isoform specifically binds with CtBPs with multifuctions such as repressor, golgi fission, and synapticvesicle fusion. The novel isoform may be involved in the synaptic function via binding with CtBPs. Research fund: KAKENHI (18700333).
P3-j33 Identification of a novel isoform of Foxp2 located in the cytoplasm of mouse developing Purkinje cells Ayumi Matsuzaki 1,2 , Yuko Tanabe 1 , Eriko Fujita 1 , Tadashi Kasahara 2 , Takashi Momoi 1 1 Department of Inherited Metabolic Diseases, NCNP, Tokyo, Japan; 2 Department of Biochemistry, Kyoritsu University of Pharmacy, Tokyo, Japan FOXP2 belongs to a newly identified subfamily of Forkhead box (FOX)transcription factors. The mutations of FOXP2 have been detected in the family of the speech/language disorder, suggesting that FOXP2 is involved in acquiring human speech/language ability. In contrast with wild type, the mutated FOXP2s are located in the cytoplasm. In the present study, we identified the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depends on two distally separated nuclear localization signals in the forkhead domain. Furthermore, we identified the novel isofrom lacking forkhead domain located in the cytoplasm during mouse brain development. In the mouse cerebellum, this novel isoform was mainly detected in the cytoplasm of the Purkinje cells (P2-P10), but not in those of P15-P22. This novel isoform may be involved in the acquiring mouse “singing” ability related to the human speech/language ability.
P3-j35 Perinatal BPA exposure impairs synaptic architectures and functions in the hippocampus of offspring Ling Chen 1 , Masahiro Sokabe 2,3 Dept Physiol, Nanjing Med Univ, Nanjing, China; 2 Dept Physiol, Nagoya Univ Grad Sch Med, Nagoya, Japan; 3 ICORP/SORST Cell Mechanosensing, JST, Nagoya, Japan
1
Humans are routinely exposed to the environmental estrogen bisphenol A (BPA) leaking from food and beverage containers. Exposure to low doses of BPA are known to affect a variety of animal behaviors including memory and learning. Here we report that perinatal exposure to a low dose of BPA (100 ng/kg) impaired the maze learning, and increased the spontaneous motor activities of 4 weeks male offspring. We investigated the neuronal functions and ultra-structures of the hippocampal CA1 region in these animals. Basal synaptic transmission and population spikes were significantly enhanced, whereas tetanic LTP was impaired without changes in the paired-pulse facilitation. Although the density and spatial configuration of pyramidal cells looked normal, their spines and synaptic contacts at apical dendrites were morphologically altered. These results suggest that perinatal exposure to BPA will alter the hippocampal synaptic architectures and functions, resulting in behavioral abnormalities of the offspring.
P3-j36 Effects of mitochondrial ATP-sensitive K channel opening during ischemia/reperfusion in neurons Nobuhiro Matsuoka 1 , Shigeyuki Yamada 1 , Masaaki Shizukuisi 1 , Tomiei Kazama 1 , Yasushi Kobayashi 2 , Hideyuki Ishida 3 1 Department of Anesthesiology, National Defense Medical College, Saitama, Japan; 2 Department of Anatomy and Neurobiology, National Defense Medical College, Saitama, Japan; 3 Department of Physiology, Tokai University, Kanagawa, Japan We investigated the effect of mitochondrial ATP-sensitive K (mitoKATP ) channel opening on the ability of oxygen glucose deprivation (OGD) to prevent intracellular Ca2+ ([Ca2+ ]i ) overload or ψm depolarization in rat hippocampal CA1 pyramidal cells. Acute hippocampal slices were preloaded with [Ca2+ ]i indicator or ψm indicator. Simulated ischemia was performed by subjecting to a 10-min OGD, then slices were recovered for 5 min. Relative changes in the [Ca2+ ]i and the ψm were measured by confocal system. After OGD the [Ca2+ ]i increased and the ψm deceased, but both deceased after recovery phase. Ischemic preconditioning (1-min OGD) and anti-anginal drug nicorandil dramatically reduced the [Ca2+ ]i overload and ψm depolarization resulting from OGD. These results suggest that mitoKATP channel opening might be attributed to the mechanism of neuroprotection.