title: Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation.
abstract: Protease nexin-1 (PN-1), a member of the serpin superfamily, controls the activity of extracellular serine proteases and is expressed in the brain. Mutant mice overexpressing PN-1 in brain under the control of the Thy-1 promoter (Thy 1/PN-1) or lacking PN-1 (PN-1-/-) were found to develop epileptic activity in vivo and in vitro. Theta burst-induced long-term potentiation (LTP) and NMDA receptor-mediated synaptic transmission in the CA1 field of hippocampal slices were augmented in Thy 1/PN-1 mice and reduced in PN-1-/- mice. Compensatory changes in GABA-mediated inhibition in Thy 1/PN-1 mice suggest that altered brain PN-1 levels lead to an imbalance between excitatory and inhibitory synaptic transmission.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Limited, CH-4002 Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Lüthi
authors.forename: H
authors.initials: H
authors.lastname: Van der Putten
authors.forename: F M
authors.initials: FM
authors.lastname: Botteri
authors.forename: I M
authors.initials: IM
authors.lastname: Mansuy
authors.forename: M
authors.initials: M
authors.lastname: Meins
authors.forename: U
authors.initials: U
authors.lastname: Frey
authors.forename: G
authors.initials: G
authors.lastname: Sansig
authors.forename: C
authors.initials: C
authors.lastname: Portet
authors.forename: M
authors.initials: M
authors.lastname: Schmutz
authors.forename: M
authors.initials: M
authors.lastname: Schröder
authors.forename: C
authors.initials: C
authors.lastname: Nitsch
authors.forename: J P
authors.initials: JP
authors.lastname: Laurent
authors.forename: D
authors.initials: D
authors.lastname: Monard
mesh_terms: D016564:Amyloid beta-Protein Precursor; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology*; D006624:Hippocampus / Q000502:physiology* / Q000503:physiopathology; D007700:Kinetics; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D011401:Promoter Regions, Genetic; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology; D009435:Synaptic Transmission; D018800:Thy-1 Antigens / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; D018800:Thy-1 Antigens