title: Modulation of abnormal synaptic transmission in hippocampal CA3 neurons of spontaneously epileptic rats (SERs) by levetiracetam.
abstract: Levetiracetam (LEV) inhibits partial refractory epilepsy in human, and both convulsive and absence-like seizures in the spontaneously epileptic rat (SER). Two-thirds of hippocampal CA3 neurons in SER show a long-lasting depolarization shift, with accompanying repetitive firing upon mossy fiber stimulation. This abnormal excitability is probably attributable to abnormalities in the L-type Ca(2+) channels. We performed electrophysiological studies to elucidate the mechanism underlying the antiepileptic effects of LEV via intracellular recording from the hippocampal CA3 neurons in slice preparations of SER and non-epileptic Wistar rats. LEV (100 μM) inhibited the depolarization shift with repetitive firing by mossy fiber stimulation (MFS), without affecting the first spike in SER CA3 neurons. At a higher dose (1mM), LEV suppressed the first spike in all SER neurons (including the CA3 neurons which showed only a single action potential by MFS), while the single action potential of Wistar rat CA3 neurons remained unaffected. SER CA3 neurons with MFS-induced abnormal firing exhibited a higher number of repetitive spikes when a depolarization pulse was applied in the SER CA3 neurons. LEV (100 μM, 1mM) reduced the repetitive firing induced by a depolarization pulse applied without affecting Ca(2+) spike in SER neurons. LEV is known not to bind glutamate and gamma-aminobutyric acid (GABA) receptors. These findings suggest that the therapeutic concentration of LEV inhibits abnormal firing of the CA3 neurons by modulating abnormal synaptic transmission and abnormal Na(+) channels in SER.
authors.affiliation: Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan. hanaya@m2.kufm.kagoshima-u.ac.jp
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hanaya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kiura
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurisu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Arita
authors.forename: Masashi
authors.initials: M
authors.lastname: Sasa
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D056654:CA3 Region, Hippocampal / Q000166:cytology*; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D000077287:Levetiracetam; D008564:Membrane Potentials / Q000187:drug effects; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D015222:Sodium Channels / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D015222:Sodium Channels; D000077287:Levetiracetam; D002118:Calcium; D010889:Piracetam