title: Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene.
abstract: Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines that are considered to be involved in a variety of neuropsychiatric functions. Here, we report behavioral and neuropsychological deficits in mice carrying a single mutated allele of the TH gene in which TH activity in tissues is reduced to approximately 40% of the wild-type activity. In the mice heterozygous for the TH mutation, noradrenaline accumulation in brain regions was moderately decreased to 73-80% of the wild-type value. Measurement of extracellular noradrenaline level in the frontal cortex by the microdialysis technique showed a reduction in high K(+)-evoked noradrenaline release in the mutants. The mutant mice displayed impairment in the water-finding task associated with latent learning performance. They also exhibited mild impairment in long-term memory formation in three distinct forms of associative learning, including active avoidance, cued fear conditioning, and conditioned taste aversion. These deficits were restored by the drug-induced stimulation of noradrenergic activity. In contrast, the spatial learning and hippocampal long-term potentiation were normal in the mutants. These results provide genetic evidence that the central noradrenaline system plays an important role in memory formation, particularly in the long-term memory of conditioned learning.
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. kazuto@cc.fmu.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Noda
authors.forename: N
authors.initials: N
authors.lastname: Matsushita
authors.forename: K
authors.initials: K
authors.lastname: Nishii
authors.forename: H
authors.initials: H
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Nagatsu
authors.forename: D
authors.initials: D
authors.lastname: Nakahara
authors.forename: R
authors.initials: R
authors.lastname: Fukabori
authors.forename: Y
authors.initials: Y
authors.lastname: Yasoshima
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Miura
authors.forename: M
authors.initials: M
authors.lastname: Kano
authors.forename: T
authors.initials: T
authors.lastname: Mamiya
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: T
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology; D001362:Avoidance Learning / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics; D002678:Chimera; D005239:Fear; D005260:Female; D005625:Frontal Lobe / Q000166:cytology / Q000201:enzymology; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008818:Mice, Neurologic Mutants; D017551:Microdialysis; D009474:Neurons / Q000201:enzymology; D009638:Norepinephrine / Q000378:metabolism*; D013028:Space Perception / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine