Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.
Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast to the expectation that wild-type (WT) males born to H (fmr-1(+/-)) mothers (H>WT) are behaviorally normal and indistinguishable from WT males born to WT mothers (WT>WT); here, we show that H>WT offspring are more active than WT>WT offspring and that their hyperactivity is similar to male KO mice born to H or KO (fmr-1(-/-)) mothers (H>KO/KO>KO). H>WT mice, however, do not exhibit seizures or abnormal sensory processing. Consistent with their hyperactivity, the effect of the D2 agonist quinpirole is reduced in H>WT as well as in H>KO and KO>KO mice compared to WT>WT offspring, suggesting a diminished feedback inhibition of dopamine release. Our data indicate that some aspects of hyperactivity and associated dopaminergic changes in 'fragile X' mice are a maternal fmr-1 genotype rather than an offspring fmr-1 genotype effect.
Zupan
Bojana
B
Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA.
Toth
Miklos
M
D000818:Animals; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology*; D006580:Genetic Carrier Screening; D008297:Male; D008425:Maternal Behavior / Q000502:physiology* / Q000523:psychology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D013216:Reflex, Startle / Q000235:genetics
D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse