Impaired fear extinction in mice lacking protease nexin-1
European Journal of Neuroscience. 2010-05-31; 31(11): 2033-2042
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1. Eur J Neurosci. 2010 Jun;31(11):2033-42. doi: 10.1111/j.1460-9568.2010.07221.x.
Epub 2010 May 24.
Impaired fear extinction in mice lacking protease nexin-1.
Meins M(1), Herry C, Müller C, Ciocchi S, Moreno E, Lüthi A, Monard D.
(1)Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,
CH-4058 Basel, Switzerland.
Eur J Neurosci. 2010 Jun;31(11):2032.
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.
PMID: 20529116 [Indexed for MEDLINE]