TY - JOUR T1 - Modest Neuropsychological Deficits Caused by Reduced Noradrenaline Metabolism in Mice Heterozygous for a Mutated Tyrosine Hydroxylase Gene JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2418 LP - 2426 DO - 10.1523/JNEUROSCI.20-06-02418.2000 VL - 20 IS - 6 AU - Kazuto Kobayashi AU - Yukihiro Noda AU - Natsuki Matsushita AU - Kazuhiro Nishii AU - Hirohide Sawada AU - Toshiharu Nagatsu AU - Daiichiro Nakahara AU - Ryoji Fukabori AU - Yasunobu Yasoshima AU - Takashi Yamamoto AU - Masami Miura AU - Masanobu Kano AU - Takayoshi Mamiya AU - Yoshiaki Miyamoto AU - Toshitaka Nabeshima Y1 - 2000/03/15 UR - http://www.jneurosci.org/content/20/6/2418.abstract N2 - 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. ER -