title: 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.
abstract: 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.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Sakurai
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Ko
authors.initials: K
authors.lastname: Zushida
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagamine
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006624:Hippocampus / Q000201:enzymology / Q000503:physiopathology; D007859:Learning Disabilities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001523:Mental Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D010766:Phosphorylation; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C492004:Creb1 protein, mouse; C496976:Uchl1 protein, mouse