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Metabolic and respiratory acidosis suppresses absence seizures in Cacna1a mutant rats
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Abstracts / Neuroscience Research 71S (2011) e108–e415
P3-s02 Comparison between fMRI and direct cortical stimulation for clinical retinotopic mapping Akihiro Shimotake 1 , Riki Matsumoto 1 , Masanori Kanazu 2 , Hiroki Yamamoto 2 , Masao Matsuhashi 3 , Nobukatsu Sawamoto 3 , Yukihiro Yamao 4 , Nobuhiro Mikuni 5 , Susumu Miyamoto 4 , Hidenao Fukuyama 3 , Ryosuke Takahashi 1 , Akio Ikeda 1 1
Dept Neurology, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 2 Grad Sch of Human and Environmental Studies, Kyoto Univ, Kyoto, Japan 3 HBRC, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 4 Dept Neurosurgery, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 5 Dept Neurosurgery, Sapporo Med Univ, Sapporo, Japan
Introduction: Although retinotopic mapping with functional MRI (fMRI) has developed in healthy subjects, only a few attempts have been made for clinical application to functional neurosurgery. The objective of our study is to map the visual cortices by combined use of fMRI and high frequency electrical cortical stimulation (HFECS) for the presurgical evaluation of intractable occipital lobe epilepsy (OLE). Methods: Subjects were 2 patients with intractable OLE. Pt 1 was a 26-yearold man, with an atrophic right temporo–parieto–occipital area. Pt 2 was a 22-year-old man, with a lesion in the medial part of the right occipital lobe at and around the calcarine fissure. Before surgery, both patients underwent retinotopic cortical mapping by fMRI. Subdural electrodes were placed for presurgical evaluation over the epileptogenic lesion and the visual cortices assessed by fMRI. HFECS was performed to map the visual cortices. Results: In both patients, fMRI showed the retinotopic activation in the occipital cortices corresponding to each eccentricity or angle of visual stim, though Pt 1 had less activation on the right due to atrophy. In Pt 1, HFECS revealed the cortices responsible for central vision at the ventrolateral and basal parts of the occipital pole, while those for peripheral vision was mapped on the dorsolateral part. In Pt 2, HFECS demonstrated the retinotopic representation with the cortices for central vision at the occipital pole and those for the peripheral in the surrounding area. In terms of the eccentricity and angle at the sites of electrodes, a favorable consistency (∼70%) was observed between fMRI activation and HEFCS results. Conclusions: Results of retinotopic cortical mapping by fMRI and HFECS were highly consistent. FMRI retinotopic mapping would be clinically useful for non-invasive presurgical evaluation of the visual cortices for patients with intractable OLE. doi:10.1016/j.neures.2011.07.1290
P3-s03 The effects of zinc administration on seizureinduced aberrant neurogenesis in hippocampal dentate gyrus Youichirou Higashi , Manabu Ohta, Masahiro Kitahara, Motonobu Nonaka, Toshio Yawata, Keiji Shimizu Department of Neurosurgery, Kochi Medical School, Kochi University, Kochi, Japan Aim: In rodent model of mesial temporal lobe epilepsy, seizure activities dramatically proliferate neurogenic progenitors and ectopically localize them in the hippocampal dentate gyrus (DG), and also decline cognitive function. Brain zinc is involved in the pathological conditions of epilepsy. Disruption of brain zinc homeostasis increases seizure susceptibility and contributes to seizure-induced neuron death. This study aims to determine whether zinc correlates with seizure-induced aberrant neurogenesis. Materials and methods: Status epilepticus (SE) was induced in C57BL/6 mice following with or without zinc (150 mg/L in tap water) administration for 30 days by pilocarpine (270 mg/kg). Newly born cells in the DG were labeled via daily injection of 5 -bromodeoxyuridine (BrdU) for 13 days following SE induction and DG neurogenesis was examined using BrdU, DCX and NeuN immunostaining. We also evaluated the effect of zinc administration on changes in expression of neuroprotective genes such as FGF-2 in epileptic hippocampus and SE-induced cognitive dysfunction. Results: Two weeks after pilocarpine injection, we found that zinc administration reduced ectopic hialr neurogenic progenitors, and increased newborn neuron in the granule cell layer. Furthermore, SE induced small increase in FGF-2 mRNA expression, which was significantly enhanced in zinc administration group. Analyses using a novel location test revealed SE led to cognitive dysfunction, which was reversed in zinc administration group. Conclusion: These findings suggest that zinc administration prevents SEinduced aberrant neurogenesis and cognitive dysfunction, which may be mediated by enhancement of FGF-2 expression. Research fund: KAKENHI (22791349). doi:10.1016/j.neures.2011.07.1291
P3-s04 PKC-dependent phosphorylation of SNAP-25 plays a crucial role in the suppression of epileptogenesis and anxiety-related behavior in postnatal period of mouse Shintaro Otsuka 1 , Saori Yamamori 1 , Shigeru Watanabe 2 , Eiji Suzuki 3 , Masanori Saito 2 , Hitoshi Miyaoka 2 , Masami Takahashi 1,4 1
Dept Biochemistry, Kitasato Univ Sch Med, Kanagawa, Japan 2 Dept Psychiatry, Kitasato Univ Sch Med, Kanagawa, Japan 3 Dept Psychiatry, Int Univ Health and Welfare Atami Hospital 4 CREST
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrated that protein kinase C phosphorylated Ser187 of SNAP-25, and enhanced neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. In order to know the functional roles of SNAP-25 phosphorylation in brain function, we generated a knock-in mouse with a single amino acid substitution of Ala at Ser187. We found that the mutant mouse displayed very strong anxiety-related behaviors throughout life. In order to understand the pathogenic mechanisms of these phenotypes, now we extensively analyzed the changes in behavior and neuronal activity during early postnatal period. No anxiety-related behavior was appeared until after three weeks post birth, but burst discharge of high-voltage spikes was often observed in cortical electroencephalogram of the mutant mouse. In 3–4 week after birth, spontaneous generalized seizure accompanying epileptic discharge both in cerebral cortex and hippocampus was repeatedly induced, and the anxiety-related behavior appeared several days thereafter. Administration of valproic acid, an anticonvulsant, from 16-day after birth markedly suppressed the expression of anxiety-related behavior. Quite similar anxiety-related behavior appeared at several days after status epilepticus induced by pilocarpine in wild type mouse. All of these results indicate that phosphorylation of SNAP-25 plays crucial role in the suppression of epilepsy during early postnatal period, and the anxiety-related behavior originated from changes in some kind of brain structure occurring within a few days after repeated generalized seizure. Research fund: CREST JST. doi:10.1016/j.neures.2011.07.1292
P3-s05 Metabolic and respiratory acidosis suppresses absence seizures in Cacna1a mutant rats Mamoru Ouchida 1 , Yuko Kaida 2 , Iori Ohmori 3 , Takashi Uehara 2 , Hideki Matsui 3
1 Dep. of Mol. Genet., Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan 2 Dep. of Med. Pharmac., Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan 3 Dep. of Physiology, Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan
Absence seizure is characterized by a sudden impairment of consciousness and a motionless stare which is accompanied by diffuse 3 Hz spike-and-wave bursts on EEG. Absence epilepsies have been linked to dysfunction of voltagegated calcium channels, GABAA receptors and hyperpolarization-activated cyclic nucleotide-gated channels. Here, we studied pH sensitivity to absence seizures caused by the P/Q type voltage-gated Ca2+ channel (Cacna1a) mutation. Cacna1a mutant male rats ranging from 9 to 11 weeks old were implanted with electrodes for EEG recording. Animals were given 1 week recovery period after surgery. Metabolic acidosis and alkalosis were successfully induced by peritoneal administration of acetazolamide and sodium bicarbonate, respectively. Metabolic acidosis reduced spike-and-wave discharges on EEG, whereas metabolic alkalosis did not worsen them in Cacna1a mutant rats. Inhalation of 10% CO2 induced respiratory acidosis in Cacna1a mutant rats and significantly reduced absence seizures. These results suggested that metabolic and respiratory acidosis had antiepileptic action. Research fund: KAKENHI21390312. doi:10.1016/j.neures.2011.07.1293
P3-s06 Differential antioxidant response of cortex and hippocampus in experimental model of chronic epilepsy: Protection by curcumin Harpreet Kaur , Rajat Sandhir Department of Biochemistry, Panjab University, Chandigarh, India Oxidative stress has been suggested to play an important role in the etiopathogenesis of epilepsy. The present study was conducted to evaluate the neuroprotective potential of curcumin in pentylenetetrazole (PTZ) induced chronic epilepsy. Rats were injected PTZ (40 mg/kg ip) once every alternate day (48 h) until the development of kindling. All studies were done
Abstracts / Neuroscience Research 71S (2011) e108–e415
P3-s02 Comparison between fMRI and direct cortical stimulation for clinical retinotopic mapping Akihiro Shimotake 1 , Riki Matsumoto 1 , Masanori Kanazu 2 , Hiroki Yamamoto 2 , Masao Matsuhashi 3 , Nobukatsu Sawamoto 3 , Yukihiro Yamao 4 , Nobuhiro Mikuni 5 , Susumu Miyamoto 4 , Hidenao Fukuyama 3 , Ryosuke Takahashi 1 , Akio Ikeda 1 1
Dept Neurology, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 2 Grad Sch of Human and Environmental Studies, Kyoto Univ, Kyoto, Japan 3 HBRC, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 4 Dept Neurosurgery, Grad Sch of Med, Kyoto Univ, Kyoto, Japan 5 Dept Neurosurgery, Sapporo Med Univ, Sapporo, Japan
Introduction: Although retinotopic mapping with functional MRI (fMRI) has developed in healthy subjects, only a few attempts have been made for clinical application to functional neurosurgery. The objective of our study is to map the visual cortices by combined use of fMRI and high frequency electrical cortical stimulation (HFECS) for the presurgical evaluation of intractable occipital lobe epilepsy (OLE). Methods: Subjects were 2 patients with intractable OLE. Pt 1 was a 26-yearold man, with an atrophic right temporo–parieto–occipital area. Pt 2 was a 22-year-old man, with a lesion in the medial part of the right occipital lobe at and around the calcarine fissure. Before surgery, both patients underwent retinotopic cortical mapping by fMRI. Subdural electrodes were placed for presurgical evaluation over the epileptogenic lesion and the visual cortices assessed by fMRI. HFECS was performed to map the visual cortices. Results: In both patients, fMRI showed the retinotopic activation in the occipital cortices corresponding to each eccentricity or angle of visual stim, though Pt 1 had less activation on the right due to atrophy. In Pt 1, HFECS revealed the cortices responsible for central vision at the ventrolateral and basal parts of the occipital pole, while those for peripheral vision was mapped on the dorsolateral part. In Pt 2, HFECS demonstrated the retinotopic representation with the cortices for central vision at the occipital pole and those for the peripheral in the surrounding area. In terms of the eccentricity and angle at the sites of electrodes, a favorable consistency (∼70%) was observed between fMRI activation and HEFCS results. Conclusions: Results of retinotopic cortical mapping by fMRI and HFECS were highly consistent. FMRI retinotopic mapping would be clinically useful for non-invasive presurgical evaluation of the visual cortices for patients with intractable OLE. doi:10.1016/j.neures.2011.07.1290
P3-s03 The effects of zinc administration on seizureinduced aberrant neurogenesis in hippocampal dentate gyrus Youichirou Higashi , Manabu Ohta, Masahiro Kitahara, Motonobu Nonaka, Toshio Yawata, Keiji Shimizu Department of Neurosurgery, Kochi Medical School, Kochi University, Kochi, Japan Aim: In rodent model of mesial temporal lobe epilepsy, seizure activities dramatically proliferate neurogenic progenitors and ectopically localize them in the hippocampal dentate gyrus (DG), and also decline cognitive function. Brain zinc is involved in the pathological conditions of epilepsy. Disruption of brain zinc homeostasis increases seizure susceptibility and contributes to seizure-induced neuron death. This study aims to determine whether zinc correlates with seizure-induced aberrant neurogenesis. Materials and methods: Status epilepticus (SE) was induced in C57BL/6 mice following with or without zinc (150 mg/L in tap water) administration for 30 days by pilocarpine (270 mg/kg). Newly born cells in the DG were labeled via daily injection of 5 -bromodeoxyuridine (BrdU) for 13 days following SE induction and DG neurogenesis was examined using BrdU, DCX and NeuN immunostaining. We also evaluated the effect of zinc administration on changes in expression of neuroprotective genes such as FGF-2 in epileptic hippocampus and SE-induced cognitive dysfunction. Results: Two weeks after pilocarpine injection, we found that zinc administration reduced ectopic hialr neurogenic progenitors, and increased newborn neuron in the granule cell layer. Furthermore, SE induced small increase in FGF-2 mRNA expression, which was significantly enhanced in zinc administration group. Analyses using a novel location test revealed SE led to cognitive dysfunction, which was reversed in zinc administration group. Conclusion: These findings suggest that zinc administration prevents SEinduced aberrant neurogenesis and cognitive dysfunction, which may be mediated by enhancement of FGF-2 expression. Research fund: KAKENHI (22791349). doi:10.1016/j.neures.2011.07.1291
P3-s04 PKC-dependent phosphorylation of SNAP-25 plays a crucial role in the suppression of epileptogenesis and anxiety-related behavior in postnatal period of mouse Shintaro Otsuka 1 , Saori Yamamori 1 , Shigeru Watanabe 2 , Eiji Suzuki 3 , Masanori Saito 2 , Hitoshi Miyaoka 2 , Masami Takahashi 1,4 1
Dept Biochemistry, Kitasato Univ Sch Med, Kanagawa, Japan 2 Dept Psychiatry, Kitasato Univ Sch Med, Kanagawa, Japan 3 Dept Psychiatry, Int Univ Health and Welfare Atami Hospital 4 CREST
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrated that protein kinase C phosphorylated Ser187 of SNAP-25, and enhanced neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. In order to know the functional roles of SNAP-25 phosphorylation in brain function, we generated a knock-in mouse with a single amino acid substitution of Ala at Ser187. We found that the mutant mouse displayed very strong anxiety-related behaviors throughout life. In order to understand the pathogenic mechanisms of these phenotypes, now we extensively analyzed the changes in behavior and neuronal activity during early postnatal period. No anxiety-related behavior was appeared until after three weeks post birth, but burst discharge of high-voltage spikes was often observed in cortical electroencephalogram of the mutant mouse. In 3–4 week after birth, spontaneous generalized seizure accompanying epileptic discharge both in cerebral cortex and hippocampus was repeatedly induced, and the anxiety-related behavior appeared several days thereafter. Administration of valproic acid, an anticonvulsant, from 16-day after birth markedly suppressed the expression of anxiety-related behavior. Quite similar anxiety-related behavior appeared at several days after status epilepticus induced by pilocarpine in wild type mouse. All of these results indicate that phosphorylation of SNAP-25 plays crucial role in the suppression of epilepsy during early postnatal period, and the anxiety-related behavior originated from changes in some kind of brain structure occurring within a few days after repeated generalized seizure. Research fund: CREST JST. doi:10.1016/j.neures.2011.07.1292
P3-s05 Metabolic and respiratory acidosis suppresses absence seizures in Cacna1a mutant rats Mamoru Ouchida 1 , Yuko Kaida 2 , Iori Ohmori 3 , Takashi Uehara 2 , Hideki Matsui 3
1 Dep. of Mol. Genet., Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan 2 Dep. of Med. Pharmac., Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan 3 Dep. of Physiology, Grad. Sch. of Med., Dent., and Pharmac. Sci., Okayama Univ., Okayama, Japan
Absence seizure is characterized by a sudden impairment of consciousness and a motionless stare which is accompanied by diffuse 3 Hz spike-and-wave bursts on EEG. Absence epilepsies have been linked to dysfunction of voltagegated calcium channels, GABAA receptors and hyperpolarization-activated cyclic nucleotide-gated channels. Here, we studied pH sensitivity to absence seizures caused by the P/Q type voltage-gated Ca2+ channel (Cacna1a) mutation. Cacna1a mutant male rats ranging from 9 to 11 weeks old were implanted with electrodes for EEG recording. Animals were given 1 week recovery period after surgery. Metabolic acidosis and alkalosis were successfully induced by peritoneal administration of acetazolamide and sodium bicarbonate, respectively. Metabolic acidosis reduced spike-and-wave discharges on EEG, whereas metabolic alkalosis did not worsen them in Cacna1a mutant rats. Inhalation of 10% CO2 induced respiratory acidosis in Cacna1a mutant rats and significantly reduced absence seizures. These results suggested that metabolic and respiratory acidosis had antiepileptic action. Research fund: KAKENHI21390312. doi:10.1016/j.neures.2011.07.1293
P3-s06 Differential antioxidant response of cortex and hippocampus in experimental model of chronic epilepsy: Protection by curcumin Harpreet Kaur , Rajat Sandhir Department of Biochemistry, Panjab University, Chandigarh, India Oxidative stress has been suggested to play an important role in the etiopathogenesis of epilepsy. The present study was conducted to evaluate the neuroprotective potential of curcumin in pentylenetetrazole (PTZ) induced chronic epilepsy. Rats were injected PTZ (40 mg/kg ip) once every alternate day (48 h) until the development of kindling. All studies were done