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Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.

ABSTRACT: 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.

SUBMITTER: Zupan B

PROVIDER: S-EPMC2904748 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.

Zupan Bojana B Toth Miklos M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20080102 11

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 ...[more]

PMID: 18172434

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Project description:The needs of offspring change as they develop. Thus, parents should concomitantly change their investment based on the age-related needs of the offspring as they mature. Due to the high costs of parental care, it is optimal for parents to exhibit a shift from intense caregiving of young offspring to promoting independence in older offspring. Yet, the neural mechanisms that underlie shifts in parental behavior are poorly understood, and little is known about how the parental brain responds to offspring of different ages. To elucidate mechanisms that relate to shifts in parental behavior as offspring develop, we examined behavioral and neural responses of male and female prairie voles (Microtus ochrogaster), a biparental rodent, to interactions with offspring at different stages of development (ranging from neonatal to weaning age). Importantly, in biparental species, males and females may adjust their behavior differentially as offspring develop. Because the nonapeptides, vasopressin (VP) and oxytocin (OT), are well known for modulating aspects of parental care, we focused on functional activity of distinct VP and OT cell groups within the maternal and paternal brain in response to separation from, reunion (after a brief period of separation) with, or no separation from offspring of different ages. We found several differences in the neural responses of individual VP and OT cell groups that varied based on the age of pups and sex of the parent. Hypothalamic VP neurons exhibit similar functional responses in both mothers and fathers. However, hypothalamic and amygdalar OT neurons exhibit differential functional responses to being separated from pups based on the sex of the parent. Our results also reveal that the developmental stage of offspring significantly impacts neural function within OT, but not VP, cell groups of both mothers and fathers. These findings provide insight into the functional plastic capabilities of the nonapeptide system, specifically in relation to parental behavior. Identifying neural mechanisms that exhibit functional plasticity can elucidate one way in which animals are able to shift behavior on relatively short timescales in order to exhibit the most context-appropriate and adaptive behaviors.

Project description:Fragile X syndrome (FXS), is an X-linked inherited genetic disease. FXS is the leading cause of inherited intellectual disability and autism in the world. Those affected are characterized by intellectual disability, language deficit, typical facies, and macroorchidism. Alterations in the FMR1 gene have been associated with FXS. The majority of people with this condition have an allele with an expansion of more than 200 repeats in a tract of CGGs within the 5' untranslated region, and this expansion is associated with a hypermethylated state of the gene promoter. FXS has incomplete penetrance and variable expressivity. Intellectual disability is present in 100% of males and 60% of females. Autism spectrum disorder symptoms appear in 50% to 60% of males and 20% of females. Other characteristics such as behavioral and physical alterations have significant variations in presentation frequency. The molecular causes of the variable phenotype in FXS patients are becoming clear: these causes are related to the FMR1 gene itself and to secondary, modifying gene effects. In FXS patients, size and methylation mosaicisms are common. Secondary to mosaicism, there is a variation in the quantity of FMR1 mRNA and the protein coded by the gene Fragile Mental Retardation Protein (FMRP). Potential modifier genes have also been proposed, with conflicting results. Characterizing patients according to CGG expansion, methylation status, concentration of mRNA and FMRP, and genotypification for possible modifier genes in a clinical setting offers an opportunity to identify predictors for treatment response evaluation. When intervention strategies become available to modulate the course of the disease they could be crucial for selecting patients and identifying the best therapeutic intervention. The purpose of this review is to present the information available about the molecular causes of the variability of the expression incomplete penetrance and variable expressivity in FXS and their potential clinical applications.

Dataset Information

Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.

Publications

Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.

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