Mouse Study of Fragile X Reflects Patients’ Abnormal Sleep Structure

Iqra Mumal, MSc avatar

by Iqra Mumal, MSc |

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A mouse model of fragile X syndrome reinforces the abnormal sleep structure observed in fragile X patients, revealing likely adverse consequences for memory processes, a study has found.

The study, “Abnormal Sleep Architecture and Hippocampal Circuit Dysfunction in a Mouse Model of Fragile X Syndrome,” was published in the journal Neuroscience.

Fragile X syndrome patients display myriad symptoms, including sleep dysfunction, that are suggestive of hyperactivity in their brain circuits.

Sleep abnormalities have been shown in both young and older children with fragile X, particularly a deficit in rapid eye movement (REM) sleep. REM is one of the five stages of sleep, within the first 90 minutes of falling asleep, where the eyes move rapidly in various directions. It accounts for 20 to 25% of an adult’s sleep cycle, and over 50% of an infant’s.

Animal models of fragile X, including flies and rodents, display irregular circadian activity  — the biological 24-hour cycle  — and sleep duration. However, it is not known whether the sleep structure and the progression and duration of sleep stages are also affected in fragile X mice.

Sleep plays an important role in cognition and memory. Brain activity that regulates memory consolidation (stabilizing a memory after its initial acquisition) occurs during sleep. Fragile X mice have deficiencies in memory consolidation, cognitive flexibility, and working memory.

Johns Hopkins researchers investigated the sleep architecture in fragile X mice as well as hippocampal neural (nerve cell) activity during sleep. The hippocampus is the part of the brain associated with memory, especially long-term memory.

The team analyzed activity from 393 hippocampal neurons (in the CA1 region of the hippocampus) in freely moving and behaving fragile X and wild-type (healthy) mice during one-hour sessions of free exploration in a familiar “home cage” environment. The CA1 region is the main output region of the hippocampus whose activity changes  during sleep-dependent memory consolidation.

Researchers used behavior and local field potential (LFP) data (a summation of excitatory and inhibitory signals from a large number of neurons) to identify distinct wake and sleep states. Excitatory and inhibitory neural signals are the “yin and yang” of the brain. Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire. This is the basis of communication among nerve cells in the brain.

Fragile X mice had reduced REM sleep periods — similar to the sleep structure experienced by fragile X patients — and their hippocampal nerve cells were hyperactive in all sleep and wake states.

Fragile X mice also displayed abnormal SWRs neuronal activity. SWRs, which stands for sharp waves and ripples, are patterns in the mammalian brain hippocampus that are seen on an electroencephalogram (EEG) during periods of immobility and sleep. SWRs are linked to memory consolidation and other memory processes.

“These results suggest abnormal neuronal activity in the Fmr1-KO mouse during SWRs, and hyperactivity during other wake and sleep states, with likely adverse consequences for memory processes,” the authors wrote.

“Despite the limitations of our methods, the aberrant structure of sleep in the [fragile X] mouse reflected aspects of the abnormal sleep architecture previously reported in FXS patients,” they concluded.