 |
||||
|
||||
|
||||
|
||||
The Journal of Neuroscience, March 15, 2000, 20(6):2418-2426
Modest Neuropsychological Deficits Caused by Reduced Noradrenaline Metabolism in Mice Heterozygous for a Mutated Tyrosine Hydroxylase Gene
Kazuto Kobayashi1, Yukihiro Noda2, Natsuki Matsushita1, Kazuhiro Nishii3, Hirohide Sawada3, Toshiharu Nagatsu3, Daiichiro Nakahara4, Ryoji Fukabori5, Yasunobu Yasoshima5, Takashi Yamamoto5, Masami Miura6, Masanobu Kano6, Takayoshi Mamiya2, Yoshiaki Miyamoto2, and Toshitaka Nabeshima2 1 Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, 2 Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya 466-8560, Japan, 3 Institute for Comprehensive Medical Science, Graduate School of Medicine, Fujita Health University, Toyoake 470-1192, Japan, 4 Department of Psychology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan, 5 Department of Behavioral Physiology, Faculty of Human Sciences, Osaka University, Suita 565-0871, Japan, and 6 Department of Physiology, Kanazawa University School of Medicine, Kanazawa 920-8640, Japan
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.
Key words: tyrosine hydroxylase; noradrenaline system; latent learning; associative learning; long-term memory; gene targeting
Copyright © 2000 Society for Neuroscience 0270-6474/00/2062418-09$05.00/0
|
|
|
|
 |
|