Dataset Information

Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome.

ABSTRACT: Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS. We identify a robust cognitive impairment in these mice that may be related to the deficits in cognitive flexibility observed in individuals with FXS. In addition, we report that levels of proteins involved in synaptic function, including the NMDA receptor subunits NR1, NR2A, and NR2B; the scaffolding proteins PSD-95 and SAPAP3; and the plasticity-related gene Arc, are decreased in the prefrontal cortex of Fmr1 KO mice and are partly correlated with behavioral performance. Finally, we report that expression of c-Fos, a marker of neuronal activity, is decreased in the PFC of Fmr1 KO mice. Together, these data suggest that Fmr1 KO mice may represent a valuable animal model for the PFC-associated molecular, cellular, and behavioral abnormalities in FXS and that this model may be useful for testing the efficacy of therapeutic strategies aimed at treating the cognitive impairments in FXS.

SUBMITTER: Krueger DD

PROVIDER: S-EPMC3038768 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome.

Krueger Dilja D DD Osterweil Emily K EK Chen Stephanie P SP Tye Lynne D LD Bear Mark F MF

Proceedings of the National Academy of Sciences of the United States of America 20110124 6

Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cell ...[more]

PMID: 21262808

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Project description:Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult Fmr1 KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the Fmr1 KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the Fmr1 KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in Fmr1 KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in Fmr1 KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.

Dataset Information

Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome.

Publications

Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome.

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