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Reduction of brain GABA contents and changes in emotional behavior in mice lacking glutamic acid decarboxylase 65kDa isoform
S72
040
AUTOREGUIATlON OF HISTAMlNE RELEASE FROM RVL NR AND NlS IN THE MEDULLA OBLONGATA.
MIISUKO KANAMARU, MICHlKO IWASE, lKU0 HOMMA Dept. of Physiology,Showa Univ. School of Medicine, Shinagawa-ku,Tokyo 142-8.555. We have reported that central histamine (HA) affects tracheal tone through the sympathetic nervous system. ln this study we examined autoregulation of HA release via Ha receptors in the rostral ventrolateral medulla (RVL), raphe nuclei (I-&)and solitary nucleus (nTS) in the medulla oblongata. Rabbits were anesthetized with urethane and achloralose, paralyzed with gallamine thriethiodide, and artibcially ventilated. HA was collected by microdialysis and analyzed using high performance liquid chromatographywith fluorescence detection of o-phthalaldehydepost-column derivatization. An Hi receptorantagonist, thioperamide maleate, or thioperamide and an Hs receptor agonist, imetit dihydrobromide were perfused through microdialysis probes HA release from the RVL, nR and nTS, increased significantly with thioperamide,but did not increase signiiicantly by co-perfusionof thioperamideand imetit. These results suggest that HA release is present in the RVL, nR and nTS; that Hs receptorsare present in the RVI+ nR and nTS; and that HA release is autoregulatedwith negative feedback via H7 receptors. Autoregulation of HA may play a role of maintaining tonic output to the sympathetic nervous system.
041
MECHANISMS OF EPILEPTIC SEIZURES IN IP3RI KNOCKOUT MICE. - DEPRESSION OF GABAB RECEPTOR ACTIVITY IN HIPPOCAMPUS -
TOMOHIRO HAMADA’, KUNIO KATO’, KATSUHIKO MIKOSHIBA’.2’3 ‘Develop. Neurobiol. Lab., RIKEN Brain Science Institute, Wake, Saitama, ‘Mikoshiba Calciosignal Net Project, ERATO, JST, Meguro-ku, Tokyo, 3Dept. Mol. Neurobiol., Inst. Med. Sci., Univ. Tokyo, Minato-ku, Tokyo Inositol 1, 4, 5 - trisphosphate receptor (IP3R) is a ligand gated Ca” - release channel on intracellular Ca” store sites, and plays an important role in intracellular Ca2’signaling. Furthermore, epileptic seizures are observed at about postnatal day 15 of the IP3R type 1 (IPSRl) knockout mice. GABAergic systems have been known to implicate in pathologic neuronal activity such as epileptic seizures. In this study, we have recorded the postsynaptic GABAB and GABAA currents in cultured hippocampal neurons of IP3RI knockout mice using the whole-cell patch clamp technique to investigate whether they have an abnormality in GABAergic systems. Both of GABA currents of the homozygote, especially GABAB, were smaller than that of the wild-type. These results suggested that loss of IP3Rl activity effects on the postsynaptic GABAergic systems which could be responsible for epileptic seizures revealed in IP3R 1 knockout mice.
042
REDUCTION OF BRAIN GABA CONTENTS AND CHANGES IN EMOTIONAL BEHAVIOR IN MICE LACKING GLUTAMIC ACID DECARBOXYLASE 65kDa ISOFORM
KUNIHIKO OBATA, FENG YUN JI , OLIVER STORK, SIMONE STORK Laboratory of Neurochemistry, National Institute for Physiological Sciences, Myodaiji, Okazaki 4448585 y-Aminobutyric acid (GABA) is synthesized by glutamic acid decarboxylase (GAD) in the mammalian CNS. In order to identify any specific roles of two isoforms of GAD, GAD65 and GAD65, in GABA synthesis and neural function, we have produced GAD-deficient
mice by gene targeting. For the first 2 months after birth GAD65-knock-out
mice
maintain the normal levels of GABA in the brain and do not have noticeable defects except for slight susceptibility to seizure. In the present study on 2-4-month-old GAD65-deficient
mice, we measured GABA contents of the cerebral
(parietal) cortex, hypothalamus and amygdala and tested several emotional behaviors. GABA contents in these regions were reduced to 60% of the wild-type mice 4 months old. Forced swimming in a cylindrical pool was accelerated and the depressant effect of diazepam on escape to a dark compartment was reduced.
040
AUTOREGUIATlON OF HISTAMlNE RELEASE FROM RVL NR AND NlS IN THE MEDULLA OBLONGATA.
MIISUKO KANAMARU, MICHlKO IWASE, lKU0 HOMMA Dept. of Physiology,Showa Univ. School of Medicine, Shinagawa-ku,Tokyo 142-8.555. We have reported that central histamine (HA) affects tracheal tone through the sympathetic nervous system. ln this study we examined autoregulation of HA release via Ha receptors in the rostral ventrolateral medulla (RVL), raphe nuclei (I-&)and solitary nucleus (nTS) in the medulla oblongata. Rabbits were anesthetized with urethane and achloralose, paralyzed with gallamine thriethiodide, and artibcially ventilated. HA was collected by microdialysis and analyzed using high performance liquid chromatographywith fluorescence detection of o-phthalaldehydepost-column derivatization. An Hi receptorantagonist, thioperamide maleate, or thioperamide and an Hs receptor agonist, imetit dihydrobromide were perfused through microdialysis probes HA release from the RVL, nR and nTS, increased significantly with thioperamide,but did not increase signiiicantly by co-perfusionof thioperamideand imetit. These results suggest that HA release is present in the RVL, nR and nTS; that Hs receptorsare present in the RVI+ nR and nTS; and that HA release is autoregulatedwith negative feedback via H7 receptors. Autoregulation of HA may play a role of maintaining tonic output to the sympathetic nervous system.
041
MECHANISMS OF EPILEPTIC SEIZURES IN IP3RI KNOCKOUT MICE. - DEPRESSION OF GABAB RECEPTOR ACTIVITY IN HIPPOCAMPUS -
TOMOHIRO HAMADA’, KUNIO KATO’, KATSUHIKO MIKOSHIBA’.2’3 ‘Develop. Neurobiol. Lab., RIKEN Brain Science Institute, Wake, Saitama, ‘Mikoshiba Calciosignal Net Project, ERATO, JST, Meguro-ku, Tokyo, 3Dept. Mol. Neurobiol., Inst. Med. Sci., Univ. Tokyo, Minato-ku, Tokyo Inositol 1, 4, 5 - trisphosphate receptor (IP3R) is a ligand gated Ca” - release channel on intracellular Ca” store sites, and plays an important role in intracellular Ca2’signaling. Furthermore, epileptic seizures are observed at about postnatal day 15 of the IP3R type 1 (IPSRl) knockout mice. GABAergic systems have been known to implicate in pathologic neuronal activity such as epileptic seizures. In this study, we have recorded the postsynaptic GABAB and GABAA currents in cultured hippocampal neurons of IP3RI knockout mice using the whole-cell patch clamp technique to investigate whether they have an abnormality in GABAergic systems. Both of GABA currents of the homozygote, especially GABAB, were smaller than that of the wild-type. These results suggested that loss of IP3Rl activity effects on the postsynaptic GABAergic systems which could be responsible for epileptic seizures revealed in IP3R 1 knockout mice.
042
REDUCTION OF BRAIN GABA CONTENTS AND CHANGES IN EMOTIONAL BEHAVIOR IN MICE LACKING GLUTAMIC ACID DECARBOXYLASE 65kDa ISOFORM
KUNIHIKO OBATA, FENG YUN JI , OLIVER STORK, SIMONE STORK Laboratory of Neurochemistry, National Institute for Physiological Sciences, Myodaiji, Okazaki 4448585 y-Aminobutyric acid (GABA) is synthesized by glutamic acid decarboxylase (GAD) in the mammalian CNS. In order to identify any specific roles of two isoforms of GAD, GAD65 and GAD65, in GABA synthesis and neural function, we have produced GAD-deficient
mice by gene targeting. For the first 2 months after birth GAD65-knock-out
mice
maintain the normal levels of GABA in the brain and do not have noticeable defects except for slight susceptibility to seizure. In the present study on 2-4-month-old GAD65-deficient
mice, we measured GABA contents of the cerebral
(parietal) cortex, hypothalamus and amygdala and tested several emotional behaviors. GABA contents in these regions were reduced to 60% of the wild-type mice 4 months old. Forced swimming in a cylindrical pool was accelerated and the depressant effect of diazepam on escape to a dark compartment was reduced.