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The Journal of Neuroscience, September 15, 2001, 21(18):6993-7000
Loss of Hippocampal Serine Protease BSP1/Neuropsin Predisposes to
Global Seizure Activity
Ben
Davies1,
Ian R.
Kearns2,
Jan
Ure1,
Ceri H.
Davies2, and
Richard
Lathe1
1 Center for Genome Research and
2 Department of Neuroscience, Center for Neuroscience,
University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom
Serine proteases in the adult CNS contribute both to
activity-dependent structural changes accompanying learning and to the regulation of excitotoxic cell death. Brain serine protease 1 (BSP1)/neuropsin is a trypsin-like serine protease exclusively expressed, within the CNS, in the hippocampus and associated limbic structures. To explore the role of this enzyme, we have used gene targeting to disrupt this gene in mice. Mutant mice were viable and
overtly normal; they displayed normal hippocampal long-term synaptic
potentiation (LTP) and exhibited no deficits in spatial navigation
(water maze). Nevertheless, electrophysiological studies revealed that
the hippocampus of mice lacking this specifically expressed protease
possessed an increased susceptibility for hyperexcitability (polyspiking) in response to repetitive afferent stimulation. Furthermore, seizure activity on kainic acid administration was markedly increased in mutant mice and was accompanied by heightened immediate early gene (c-fos) expression throughout the brain. In
view of the regional selectivity of BSP1/neuropsin brain expression, the observed phenotype may selectively reflect limbic function, further
implicating the hippocampus and amygdala in controlling cortical
activation. Within the hippocampus, our data suggest that
BSP1/neuropsin, unlike other serine proteases, has little effect on
physiological synaptic remodeling and instead plays a role in limiting
neuronal hyperexcitability induced by epileptogenic insult.
Key words:
brain serine protease; BSP1; cortex; epileptiform; fos; hippocampus; kainic acid; knock-out; long-term potentiation; LTP; mouse; mutant; neuropsin; seizure; targeting
Copyright © 2001 Society for Neuroscience 0270-6474/01/21186993-08$05.00/0
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