Behavioral Testing of Progenies of Tx (Hypothyroid) and Growth Hormone-Treated Tx Rats: An Animal Model for Mental Retardation

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Abstract
Virgin Sprague-Dawley Holtzman rats were rendered Tx (hypothyroid) by radiothyroidectomy and maintained on 1.0 .mu.g T4 (thyroxine) per 100 g BW [body weight] until pregnant. One-half of these Tx animals were administered 0.5 IU of growth hormone (GH) during the last 10-11 days of gestation as GH secretion is especially deficient in Tx rats. Untreated, food restricted to the level consumed by the Tx-only rats, GH-treated euthyroid and T4-treated until pregnant animals served as controls. The animals were allowed to go through parturition and each litter was reduced to no more than 6 pups by removing pups for tissue weights and protein analyses at 1 and 5 days of age. The pups were weaned at 22 days of age and 2 animals per litter were utilized for behavioral testing between 40 and 60 days of age. At the end of the behavioral testing period the 60-day-old offspring were sacrificed to obtain tissue weights and protein concentrations. The behavioral tests were based on the ability of the animals to learn a Lashley''s type 3 enclosed alley maze and their spontaneous activity was measured in stabilimeter cages. The animals were fasted overnight on alternate days and then given a food reward on traversing the maze. This allowed for 10 separate trials in both the Lashley maze and the stabilimeters over the 20-day period from 40-60 days of age. Previous studies have shown the fetuses and progenies of Tx-only mothers to have multiple metabolic defects including reduced rates of protein synthesis and tissue concentrations. The Tx mothers have poor reproductive performance and the surviving fetuses and early neonates are growth stunted. GH treatment of the Tx mother, during the latter part of gestation, corrects some of these parameters in their offspring. The progenies of Tx mothers used were typical of those of previous reports. The numbers of live 1-day-old neonates, their body, brain and liver weights were significantly reduced as compared to controls. Brain, liver and serum protein concentrations were significantly depressed in 1-, 5- and 60-day-old offspring of Tx-only mothers as compared to those of GH-treated and offspring of the various control group mothers. These offspring of Tx-only mothers showed a total inability to learn the Lashley maze. None of the offspring of Tx-only mothers were able to traverse the maze on consecutive trials without committing errors as compared to 25-42% of the progenies of the control groups which learned the maze before the end of 10 trials. The time required, for the offspring of all maternal groups, to traverse the maze to obtain a food reward decreased significantly. The offspring of Tx-only mothers, even though they would try to traverse the maze rapidly, took significantly longer to traverse the maze than progenies of the control groups in trials 6-10 because of the errors committed. These same offspring of the Tx-only mothers, indicating hyperactivity. The offspring of Tx-only mothers are an appropriate animal model for studying mental retardation. These animals have numerous metabolic abnormalities including impaired amino acid transport and utilization, and depressed brain protein synthesis which are common to a high percentage of human mental retardation cases. These animals also have mental dificiencies as exemplified by a lack of memory and hyperactivity.