The Journal of Neuroscience, July 15, 1999, 19(14):6175-6182
Cognitive Deficits in a Genetic Mouse Model of the Most Common
Biochemical Cause of Human Mental Retardation
Leze
Zagreda1,
Jason
Goodman1,
Donald P.
Druin1,
David
McDonald2, and
Adele
Diamond1
1 Center for Developmental Cognitive Neuroscience,
Eunice Kennedy Shriver Center, Waltham, Massachusetts 02452, and
2 Department of Biological Sciences, Wichita State
University, Wichita, Kansas 67260-0026
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 impairments. PKU mice were impaired on both odor
discrimination reversal and latent learning compared with heterozygote
littermates 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 containers 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
evidence 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; reversal
learning; latent learning; odor discrimination; mice; learning set; memory; animal models
Copyright © 1999 Society for Neuroscience 0270-6474/99/19146175-08$05.00/0
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