Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

Abstract

Fragile X syndrome (FXS) is the most common single gene (FMR1) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1-knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.

Advances in behavioral genetics: mouse models of autism

“…Similar impairments in sensorimotor gating have also been reported in adults with autism 67 or Asperger syndrome. 68 Parallel studies conducted by Frankland et al 66 confirmed that the Fmr1-null mice have enhanced prepulse inhibition of acoustic startle responses, in line with previous findings. 49,63 In addition, the Fmr1-null mice also had enhanced learning in complex operant conditioning tasks.…”

“…51 This would not explain behavioral changes in the Fmr1-null mice that are opposite to those associated with FXS and autism. For example, Frankland et al 66 reported that human subjects with FXS showed marked deficits in prepulse inhibition of acoustic startle responses. Similar impairments in sensorimotor gating have also been reported in adults with autism 67 or Asperger syndrome.…”

“…49,63 In addition, the Fmr1-null mice also had enhanced learning in complex operant conditioning tasks. 66,69 These divergent findings underscore the premise that mouse models may not reflect all components of a human clinical syndrome; however, recapitulating endophenotypes can allow exploration of neuropathology underlying specific behavioral alterations in the disease symptomatology. 70 The Mecp2-mutant mouse Rett syndrome is characterized by normal development in the first months of life, followed by regression of social, language, and cognitive function, and the emergence of unusual, stereotyped hand movements, gait and other motoric impairment, and decrements in brain growth.…”

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

“…One indication supporting the former possibility is the recent report that PPI is normal in effectively treated, non-manic patients with childhood bipolar disorder (Rich et al, 2005). In additional studies prompted in part by suggested genetic contributions to schizophrenia or related disorders, deficits in PPI have also been identified in children with 22q deletion syndrome (Sobin et al, 2005), young persons with Fragile X syndrome (Frankland et al, 2004), and adults with Asperger's syndrome (McAlonan et al, 2002), seizure disorder (Pouretemad et al, 1998), or Lewy body dementia (Perriol et al, 2005).…”

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

“…The extent to which an animal inhibits the subsequent startle response is thought to reflect the animal's ability to automatically filter out extraneous sensory information . Reduced PPI has been observed in several psychiatric and neurological illnesses, includingFbut not limited toFautism (Perry et al, 2006), Fragile X syndrome (Frankland et al, 2004), panic disorder (Ludewig et al, 2005), manic depression (Perry et al, 2001), obsessive compulsive disorder (Hoenig et al, 2005), Huntingtons' disease (Swerdlow et al, 1995), schizophrenia (Braff et al, 1978), and Tourette's syndrome (Castellanos et al, 1996). PPI deficits are particularly relevant to the study of schizophrenia and Tourette's syndrome because the ability of a drug to increase PPI in rodents predicts the clinical efficacy of medications specifically used to treat these patient populations (Swerdlow and Geyer, 1998;Geyer et al, 2001;Sandor, 2003).…”