Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene.
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.
Kobayashi
K
K
Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. kazuto@cc.fmu.ac.jp
Noda
Y
Y
Matsushita
N
N
Nishii
K
K
Sawada
H
H
Nagatsu
T
T
Nakahara
D
D
Fukabori
R
R
Yasoshima
Y
Y
Yamamoto
T
T
Miura
M
M
Kano
M
M
Mamiya
T
T
Miyamoto
Y
Y
Nabeshima
T
T
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
D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine