Prepulse inhibition in fragile X syndrome: Feasibility, reliability, and implications for treatment

Hessl, David; Berry‐Kravis, Elizabeth; Cordeiro, Lisa; Yuhas, Jennifer; Ornitz, Edward M.; Campbell, Aaron; Chruscinski, Elizabeth; Hervey, Crystal; Long, James M.; Hagerman, Randi J.

doi:10.1002/ajmg.b.30858

Cited by 70 publications

(78 citation statements)

References 64 publications

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“…Furthermore, one study in Fmr1 KO mice has shown decreased PPI of startle eyelid responses with the magnetic distance measurement [23]. This correlates with findings in humans with FXS [54,55], and thus supports a role for FMRP in sensorimotor processing both in humans and mice. Interestingly, recent studies using THIP, which we have shown to have amygdala effects [18], have also demonstrated the existence of a potent tonic inhibitory neurotransmission in the rat auditory thalamus [56] and in the avian nucleus laminaris [57], suggesting an active role of tonic inhibition in modulating auditory processing cues.…”

Section: Discussionsupporting

confidence: 61%

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

2011

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Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA_A receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.

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Section: Discussionsupporting

confidence: 61%

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

2011

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“…We also suggest that outcome measures that have been documented to be abnormal in fragile X syndrome, and have been shown to be helpful in other targeted treatment trials in fragile X syndrome, should be utilized for controlled trials of minocycline (Berry-Kravis et al, 2009; Farzin, Rivera, & Hessl, 2009; Farzin, Whitney, Hagerman, & Rivera, 2008; Hessl et al, 2009). Such quantitative measures include prepulse inhibition, which is a neurophysiological assessment of frontal gating.…”

Section: Discussionmentioning

confidence: 99%

Side Effects of Minocycline Treatment in Patients With Fragile X Syndrome and Exploration of Outcome Measures

Utari

Chonchaiya

Rivera

et al. 2010

American Journal on Intellectual and Developmental Disabilities

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Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.

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“…Fragile X syndrome, caused by a mutation in FMRI gene at Xq27.3, which prevents normal transcription with subsequent reduction/absence of FMRI protein (Tamanini et al 1997), and aberrant dendritic arborization and synaptic plasticity (Irwin et al 2000;Galvez and Greenough 2005), presents serious cognitive deficits and behavioral retardation (Cornish et al 2001;Hoeft et al 2007;Mercaldo et al 2009;Sharma et al 2009). Hessl et al (2009) assessed PPI of the startle reflex in 61 individuals with the fragile X full mutation (40 males and 21 females) with 63 age-matched normal healthy controls. They found that, in comparison with normal controls, fragile X individuals displayed PPI impairments of 26, 22, and 28% for the 60, 120, and 240 ms prepulse interval trial types, respectively, with markedly high levels of test-retest reliability.…”

Section: Epigenetics and Prepulse Inhibitionmentioning

confidence: 99%

Epigenetics and Biomarkers in the Staging of Neuropsychiatric Disorders

et al. 2010

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Epigenetics, or alterations in the phenotype or gene expression due to mechanisms other than changes in the underlying DNA sequence, reflects the sensitivity and responsiveness of human and animal brains in constantly varying circumstances regulating gene expression profiles that define the biomarkers and present the ultimate phenotypical outcomes, such as cognition and emotion. Epigenetics is associated with functionally relevant alterations to the genome in such a fashion that under the particular conditions of early, adolescent, and adult life, environmental signals may activate intracellular pathways that remodel the "epigenome," triggering changes in gene expression and neural function. Thus, genetic influences in neuropsychiatric disorders that are subject to clinical staging, epigenetics in schizophrenia, epigenetic considerations in the expression of sensorimotor gating resulting from disease conditions, biomarkers of drug use and addiction, current notions on the role of dopamine in schizophrenia spectrum disorders, and the discrete interactions of biomarkers in persistent memory were to greater or lesser extents reflected upon. The relative contributions of endophenotypes and epistasis for mediating epigenetic phenomena and the outcomes as observed in the analysis of biomarkers appear to offer a multitude of interactive combinations to further complicate the labyrinthine machinations of diagnosis, intervention, and prognosis.

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Prepulse inhibition in fragile X syndrome: Feasibility, reliability, and implications for treatment

Cited by 70 publications

References 64 publications

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

Side Effects of Minocycline Treatment in Patients With Fragile X Syndrome and Exploration of Outcome Measures

Epigenetics and Biomarkers in the Staging of Neuropsychiatric Disorders

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