Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation.
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.
Lüthi
A
A
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Limited, CH-4002 Basel, Switzerland.
Van der Putten
H
H
Botteri
F M
FM
Mansuy
I M
IM
Meins
M
M
Frey
U
U
Sansig
G
G
Portet
C
C
Schmutz
M
M
Schröder
M
M
Nitsch
C
C
Laurent
J P
JP
Monard
D
D
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
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