title: Programming social behavior by the maternal fragile X protein.
abstract: The developing fetus and neonate are highly sensitive to maternal environment. Besides the well-documented effects of maternal stress, nutrition and infections, maternal mutations, by altering the fetal, perinatal and/or early postnatal environment, can impact the behavior of genetically normal offspring. Mutation/premutation in the X-linked FMR1 (encoding the translational regulator FMRP) in females, although primarily responsible for causing fragile X syndrome (FXS) in their children, may also elicit such maternal effects. We showed that a deficit in maternal FMRP in mice results in hyperactivity in the genetically normal offspring. To test if maternal FMRP has a broader intergenerational effect, we measured social behavior, a core dimension of neurodevelopmental disorders, in offspring of FMRP-deficient dams. We found that male offspring of Fmr1(+/-) mothers, independent of their own Fmr1 genotype, exhibit increased approach and reduced avoidance toward conspecific strangers, reminiscent of 'indiscriminate friendliness' or the lack of stranger anxiety, diagnosed in neglected children and in patients with Asperger's and Williams syndrome. Furthermore, social interaction failed to activate mesolimbic/amygdala regions, encoding social aversion, in these mice, providing a neurobiological basis for the behavioral abnormality. This work identifies a novel role for FMRP that extends its function beyond the well-established genetic function into intergenerational non-genetic inheritance/programming of social behavior and the corresponding neuronal circuit. As FXS premutation and some psychiatric conditions that can be associated with reduced FMRP expression are more prevalent in mothers than full FMR1 mutation, our findings potentially broaden the significance of FMRP-dependent programming of social behavior beyond the FXS population.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.|Department of Psychology, Vassar College, Poughkeepsie, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zupan
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Psychology, Vassar College, Poughkeepsie, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Frazier
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: M
authors.initials: M
authors.lastname: Toth
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology; D000818:Animals; D044127:Epigenesis, Genetic; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D008032:Limbic System / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D012919:Social Behavior
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
keywords: Amygdala; behavioral programming; dopamine; fragile X mental retardation protein; maternal effect; mice; neural circuit; neurodevelopmental disorders; social behavior; social behavior disorders