Hyperactivity and learning deficits in transgenic mice bearing a human mutant thyroid hormone beta1 receptor gene.
Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor beta (TRbeta) gene on chromosome 3, representing a mutation of the ligand-binding domain of the TRbeta gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRbeta gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRbeta gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.
McDonald
M P
MP
Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wong
R
R
Goldstein
G
G
Weintraub
B
B
Cheng
S Y
SY
Crawley
J N
JN
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D003216:Conditioning, Operant; D005106:Exploratory Behavior; D005260:Female; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D011597:Psychomotor Performance; D011930:Reaction Time; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D012054:Reinforcement, Psychology; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics
D011988:Receptors, Thyroid Hormone