Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene

Kazuto Kobayashi, Yukihiro Noda, Natsuki Matsushita, Kazuhiro Nishii, Hirohide Sawada, Toshiharu Nagatsu, Daiichiro Nakahara, Ryoji Fukabori, Yasunobu Yasoshima, Takashi Yamamoto, Masami Miura, Masanobu Kano, Takayoshi Mamiya, Yoshiaki Miyamoto, Toshitaka Nabeshima

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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 ~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.

Original languageEnglish
Pages (from-to)2418-2426
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number6
DOIs
Publication statusPublished - 15-03-2000

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Kobayashi, K., Noda, Y., Matsushita, N., Nishii, K., Sawada, H., Nagatsu, T., Nakahara, D., Fukabori, R., Yasoshima, Y., Yamamoto, T., Miura, M., Kano, M., Mamiya, T., Miyamoto, Y., & Nabeshima, T. (2000). Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene. Journal of Neuroscience, 20(6), 2418-2426. https://doi.org/10.1523/jneurosci.20-06-02418.2000