title: Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.
abstract: Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA), suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.
authors.affiliation: Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Fukushima
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Nakao
authors.forename: Toru
authors.initials: T
authors.lastname: Shinoe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kataoka
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000166:cytology*; D053444:Inhibitory Postsynaptic Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency* / Q000502:physiology; D012640:Seizures; D009435:Synaptic Transmission
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate