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Eur J Neurosci. 2008 Feb;27(3):691-701. doi: 10.1111/j.1460-9568.2008.06047.x.

Reduction in memory in passive avoidance learning, exploratory behaviour and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene.

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Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.


Overexpression of ubiquitin C-terminal hydrolase L1 (UCH-L1) in mice rescues amyloid beta-protein-induced decreases in synaptic plasticity and memory. However, the physiological role of UCH-L1 in the brain is not fully understood. In the present study, we investigated the role of UCH-L1 in the brain by utilizing gracile axonal dystrophy (gad) mice with a spontaneous deletion in the gene Uch-l1 as a loss-of-function model. Although gad mice exhibit motor paresis beginning at approximately 12 weeks of age, it is possible to analyse their brain phenotypes at a younger age when no motor paresis is evident. Maintenance of memory in a passive avoidance test and exploratory behaviour in an open field test were reduced in 6-week-old gad mice. The maintenance of theta-burst stimulation-induced long-term potentiation (LTP) of field synaptic responses from Schaffer collaterals to CA1 pyramidal cells in hippocampal slices was also impaired in gad mice. The LTP in gad mice was insensitive to actinomycin D, suggesting that a transcription-dependent component of the LTP is impaired. Phosphorylation of cyclic AMP response element binding protein (CREB) in the CA1 region of hippocampal slices from gad mice occurred earlier than in the slices from wild-type mice and was transient, suggesting that CREB phosphorylation is altered in gad mice. These results suggest that memory in passive avoidance learning, exploratory behaviour and hippocampal CA1 LTP are reduced in gad mice. We propose that UCH-L1-mediated maintenance of the temporal integrity and persistence of CREB phosphorylation underlies these impairments.

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