Impaired fear extinction in mice lacking protease nexin-1.
The serine protease inhibitor protease-nexin-1 (PN-1) has been shown to modulate N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic currents and NMDAR-dependent long-term potentiation of synaptic transmission. Here, we analysed the role of PN-1 in the acquisition and extinction of classical auditory fear conditioning, two distinct forms of learning that both depend on NMDAR activity in the amygdala. Immunostaining revealed that PN-1 is expressed throughout the amygdala, primarily in gamma-aminobutyric acid containing neurons of the central amygdala and intercalated cell masses (ITCs) and in glia. Fear extinction was severely impaired in mice lacking PN-1 (PN-1 KO). Consistent with a role for the basal nucleus of the amygdala in fear extinction, we found that, compared with wild-type (WT) littermate controls, PN-1 KO mice exhibited decreased numbers of Fos-positive neurons in the basal nucleus after extinction. Moreover, immunoblot analysis of laser-microdissected amygdala sub-nuclei revealed specific extinction-induced increases in the level of phosphorylated alpha-calcium/calmodulin protein kinase II in the medial ITCs and in the lateral subdivision of the central amygdala in WT mice. These responses were altered in PN-1 KO mice. Together, these data indicate that lack of extinction in PN-1 KO mice is associated with distinct changes in neuronal activity across the circuitry of the basal and central nuclei and the ITCs, supporting a differential impact on fear extinction of these amygdala substructures. They also suggest a new role for serine protease inhibitors such as PN-1 in modulating fear conditioning and extinction.
Meins
Marita
M
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Herry
Cyril
C
Müller
Christian
C
Ciocchi
Stéphane
S
Moreno
Eliza
E
Lüthi
Andreas
A
Monard
Denis
D
D000679:Amygdala / Q000166:cytology / Q000502:physiology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003214:Conditioning, Classical / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2