Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

Abstract

Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical longterm potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.cortical long-term potentiation ͉ spine morphology ͉ trace fear conditioning ͉ autism F ragile X syndrome (FXS), the most commonly inherited form of mental retardation and the most common cause of autism, is caused by the loss of the fragile X mental retardation protein (FMRP) encoded by the fragile X mental retardation 1 (FMR1) gene (1). Although moderate to severe mental retardation and a developmental delay are the key features of FXS, patients also display problems related to anxiety, attention deficit, hyperactivity, stereotypy, seizure, and social behavior. FMR1 knockout (KO) mice (2), which exhibit phenotypes similar to those seen in FXS in humans, have served as a useful model system for investigating how the absence of FMRP leads to the various molecular, cellular, and behavioral abnormalities observed in the disorder. Although these studies have led to valuable insights into the etiology of FXS, there has not been effective treatment of this debilitating disorder.Several key observations are strongly suggestive of a primary role of defects in dendritic spines and synaptic plasticity in the symptoms associated with FXS (3). Increased numbers of dendritic spines and an abundance of long and immature spines have been reported in FXS individuals and FMR1 KO mice (4-7). FMRP and its mRNA are found in dendrites and spines, the sites of transmission and plastic...

Advances in behavioral genetics: mouse models of autism

“…88 In addition, a recent study has shown that the genetic inhibition of a different kinase, p21-activated kinase, in the forebrain of Fmr1-null mice can fully or partially restore alterations in behavior and dendritic spine morphology. 60 These results demonstrate that gene interaction approaches can be used for the rescue, as well as the exacerbation, of specific endophenotypes relevant to neurodevelopmental disorders. However, transgenic overexpression of Mecp2 347 or Fmr1 58 in mice has been linked to detrimental effects, providing evidence that alterations of tightly regulated gene expression may have undesired consequences.…”

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

“…Adult Fmr1 KO mice and WT siblings were provided by the Tonegawa and Bear laboratories at the Picower Centre for Learning and Memory, Massachusetts Institute of Technology (MIT, Cambridge, MA). Animals were genotyped in MIT, as previously described (37). They were housed with siblings with a 14-h/10-h day/night cycle with ad libitum access to food and water.…”

Recurrent perseveration correlates with abnormal repetitive locomotion in adult mink but is not reduced by environmental enrichment

“…In this paper, we will use the term abnormal repetitive behaviour (ARB) to encompass all of these. ARB can be induced in research animals via extreme early maternal deprivation [7], treatment with psychostimulant drugs [8,9], or genetic manipulations, as in DAT knockout [10] and Fragile X models [11]. In both humans and manipulated research animals, altered functioning of the basal ganglia and corticostriatal circuits is implicated in ARB.…”