Cognitive Deficits in a Genetic Mouse Model of the Most Common Biochemical Cause of Human Mental Retardation

Phenylalanine hydroxylase (Pah)-deficient “PKU mice ” have a mutation in the Pah gene that causes phenylketonuria (PKU) in humans. PKU produces cognitive deficits in humans if it is untreated. We report here the first evidence that the genetic mouse model of PKU (Pahenu2) also produces cognitive impair-ments. PKU mice were impaired on both odor discrimination reversal and latent learning compared with heterozygote litter-mates and with wild-type mice of the same BTBR strain. A small container of cinnamon-scented sand was presented on the right or left, and nutmeg-scented sand was presented on the other side; left–right location varied over trials. Digging in sand of the correct scent was rewarded by finding phenylalanine-free chocolate. To prevent scent cuing, new con-tainers were used on every trial, and both containers always contained chocolate. Digging in the incorrect choice was stopped before the chocolate was uncovered. Once criterion was reached, the other scent was rewarded. PKU mice were impaired on reversals 2, 3, and 4. They were also impaired in latent learning. On day 1, half the mice were allowed to explore a maze and discover the location of water. On day 2, all mice were water-deprived and were placed in the maze. Whereas pre-exposed wild-type and heterozygous mice showed evi-dence that they remembered the location of the water and hence could find the water faster on day 2, pre-exposed PKU mice showed no significant benefit from their pre-exposure on day 1. Key words: PKU; phenylketonuria; mental retardation; rever-sal learning; latent learning; odor discrimination; mice; learning set; memory; animal models Phenylketonuria (PKU) is an inborn error of metabolism in which phenylalanine hydroxylase (Pah), the enzyme necessary for the hydroxylation of phenylalanine (Phe) to tyrosine is absent o