title: Epileptogenesis and epileptic maturation in phosphorylation site-specific SNAP-25 mutant mice.
abstract: Snap25(S187A/S187A) mouse is a knock-in mouse with a single amino acid substitution at a protein kinase C-dependent phosphorylation site of the synaptosomal-associated protein of 25 kDa (SNAP-25), which is a target-soluble NSF attachment protein receptor (t-SNARE) protein essential for neurotransmitter release. Snap25(S187A/S187A) mice exhibit several distinct phenotypes, including reductions in dopamine and serotonin release in the brain, anxiety-like behavior, and cognitive dysfunctions. Homozygous mice show spontaneous epileptic convulsions, and about 15% of the mice die around three weeks after birth. The remaining mice survive for almost two years and exhibit spontaneous recurrent seizures throughout their lifetime. Here, we conducted long-term continuous video electroencephalogram recording of the mice and analyzed the process of epileptogenesis and epileptic maturation in detail. Spikes and slow-wave discharges (SWDs) were observed in the cerebral cortex and thalamus before epileptic convulsions began. SWDs showed several properties similar to those observed in absence seizures including (1) lack of in the hippocampus, (2) movement arrest during SWDs, and (3) inhibition by ethosuximide. Multiple generalized seizures occurred in all homozygous mice around three weeks after birth. However, seizure generation stopped within several days, and a seizure-free latent period began. Following a spike-free quiet period, the number of spikes increased gradually, and epileptic seizures reappeared. Subsequently, spontaneous seizures occurred cyclically throughout the life of the mice, and several progressive changes in seizure frequency, seizure duration, seizure cycle interval, seizure waveform, and the number and waveform of epileptic discharges during slow-wave sleep occurred with different time courses over 10 weeks. Anxiety-related behaviors appeared suddenly within three days after epileptic seizures began and were delayed markedly by oral administration of valproic acid. These results showed that Snap25(S187A/S187A) mice exhibited a variety of epilepsy-related phenomena, and thus, they will be useful for understanding the mechanisms of epileptogenesis, epileptic maturation, and the actions of antiepileptic drugs.
authors.affiliation: Department of Psychiatry, Kitasato University School of Medicine, 2-1-1 Asamizodai, Minami-ku, Sagamihara-shi, Kanagawa, 252-0380, Japan. Electronic address: nabesige@kitasato-u.ac.jp.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara-shi, Kanagawa, 252-0374, Japan. Electronic address: yamamori@med.kitasato-u.ac.jp.
authors.forename: Saori
authors.initials: S
authors.lastname: Yamamori
authors.affiliation: Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara-shi, Kanagawa, 252-0374, Japan. Electronic address: otsuka@z6.keio.jp.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Otsuka
authors.affiliation: Department of Psychiatry, Kitasato University School of Medicine, 2-1-1 Asamizodai, Minami-ku, Sagamihara-shi, Kanagawa, 252-0380, Japan. Electronic address: 7n2ecx@mtf.biglobe.ne.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, International University of Health and Welfare Atami Hospital, Atami-shi, Shizuoka, 413-0012, Japan. Electronic address: e-suzuki@iuhw.ac.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Environmental Science and Technology, Engineering, Shinshu University, Nagano-shi, Nagano, 380-8553, Japan. Electronic address: mars@shinshu-u.ac.jp.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Department of Psychiatry, Kitasato University School of Medicine, 2-1-1 Asamizodai, Minami-ku, Sagamihara-shi, Kanagawa, 252-0380, Japan. Electronic address: miyaoka@med.kitasato-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyaoka
authors.affiliation: Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara-shi, Kanagawa, 252-0374, Japan. Electronic address: masami@med.kitasato-u.ac.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D000069280:Electrocorticography; D004567:Electrodes, Implanted; D004827:Epilepsy / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D055879:Gene Knock-In Techniques; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D017440:Photoperiod; D012640:Seizures / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D014635:Valproic Acid
keywords: Antiepileptic drug; Anxiety-like behavior; Epileptic maturation; Epileptogenesis; Mutant mouse; SNARE protein