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 b iosynthesis of catecholamines that are considered to be involved in a varie ty of neuropsychiatric functions. Here, we report behavioral and neuropsych ological deficits in mice carrying a single mutated allele of the TH gene i n which TH activity in tissues is reduced to similar to 40% of the wild-typ e activity. In the mice heterozygous for the TH mutation, noradrenaline acc umulation in brain regions was moderately decreased to 73-80% of the wild-t ype 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 dist inct forms of associative learning, including active avoidance, cued fear c onditioning, and conditioned taste aversion. These deficits were restored b y 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 noradrenal ine system plays an important role in memory formation, particularly in the long-term memory of conditioned learning.