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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
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