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. 2022 May:182:106891.
doi: 10.1016/j.eplepsyres.2022.106891. Epub 2022 Mar 8.

Spontaneous seizures in adult Fmr1 knockout mice: FVB.129P2-Pde6b+Tyrc-chFmr1tm1Cgr/J

Jessica L Armstrong  1 , Tanishka S Saraf  1 , Omkar Bhatavdekar  2 , Clinton E Canal  3
Affiliations

Spontaneous seizures in adult Fmr1 knockout mice: FVB.129P2-Pde6b+Tyrc-chFmr1tm1Cgr/J

Jessica L Armstrong et al. Epilepsy Res. 2022 May.

Abstract

The prevalence of seizures in individuals with fragile X syndrome (FXS) is ~25%; however, there are no reports of spontaneous seizures in the Fmr1 knockout mouse model of FXS. Herein, we report that 48% of adult (median age P96), Fmr1 knockout mice from our colony were found expired in their home cages. We observed and recorded adult Fmr1 knockout mice having spontaneous convulsions in their home cages. In addition, we captured by electroencephalography an adult Fmr1 knockout mouse having a spontaneous seizure-during preictal, ictal, and postictal phases-which confirmed the presence of a generalized seizure. We did not observe this phenotype in control conspecifics or in juvenile (age <P35) Fmr1 knockout mice. We hypothesized that chronic, random, noise perturbations during development caused the phenotype. We recorded decibels (dB) in our vivarium. The average was 61 dB, but operating the automatic door to the vivarium caused spikes to 95 dB. We modified the door to eliminate noise spikes, which reduced unexpected deaths to 33% in Fmr1 knockout mice raised from birth in this environment (P = 0.07). As the modifications did not eliminate unexpected deaths, we further hypothesized that building vibrations may also be a contributing factor. After installing anti-vibration pads underneath housing carts, unexpected deaths of Fmr1 knockout mice born and raised in this environment decreased to 29% (P < 0.01 compared to the original environment). We also observed significant sex effects, for example, after interventions to reduce sound and vibration, significantly fewer male, but not female, Fmr1 knockout mice died unexpectedly (P < 0.001). The spontaneous seizure phenotype in our Fmr1 knockout mice could serve as a model of seizures observed in individuals with FXS, potentially offering a new translationally-valid phenotype for FXS research. Finally, these observations, although anomalous, serve as a reminder to consider gene-environment interactions when interpreting data derived from Fmr1 knockout mice.

Keywords: EEG; Fmr1; Fragile X syndrome; Generalized seizure; Sexual Dimorphism; Spontaneous seizure.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Unexpected deaths in control (blue/left) compared to Fmr1 knockout (red/right) mice. Sound attenuation by modifying the automatic door shutting mechanism to the vivarium (“door fix”) showed a trend to decrease unexpected deaths in Fmr1 knockout mice, relative to mice born and raised in the unmodified vivarium. The addition of anti-vibration pads under housing carts significantly reduced unexpected deaths in Fmr1 knockout born and raised in this environment, compared to the unmodified vivarium. ****P<0.0001; **P<0.01.
Figure 2.
Figure 2.
Histogram showing percent of total unexpected deaths in Fmr1 knockout mice across age, and within different vivarium environments. Ages were condensed into 20-day bins, such that each bin includes ages within the 20-day range. The data points define the middle of each bin, e.g., the day 90 (P90) data point includes animals aged P80–P100. Most mice died unexpectedly between P80 and P120.
Figure 3.
Figure 3.
Sound level data recorded in the sound-attenuated vivarium once every minute, sampling across 12 days. Horizontal red arrows show defined noise perturbations, one unidentified noise perturbation, and a break in recording. The 7 am/7 pm on/off light cycle is represented by vertical red arrows. Note the rhythmic patterns in noise levels that coincide with the increase in activity levels after 7 pm when the lights were off, and a decrease in activity levels after 7 am when the lights were on.
Figure 4.
Figure 4.
Sex differences in unexpected deaths in Fmr1 knockout mice across different vivarium environments. In the original, unmodified vivarium environment, the percent of unexpected deaths was higher in Fmr1 knockout males compared to females, though differences were not statistically significant. Fixing the door to the vivarium (“door fix”) significantly reduced unexpected deaths in male Fmr1 knockout mice. The addition of anti-vibration pads resulted in a significantly lower percentage of unexpected deaths in males than females. Changes to the vivarium did not impact the percent of unexpected deaths in Fmr1 knockout females. ****P<0.0001; **P<0.01.
Figure 5.
Figure 5.
EEG recordings showing seizure activity from three channels in a male Fmr1 knockout mouse aged P96. Green traces are from signals recorded on the skull above the left somatosensory cortex; red are from the right somatosensory cortex; black are from the auditory cortex. (a) Beginning of seizure activity. A brief break in seizure activity was observed between 10.25 and 10.75 sec. (b) Peak of seizure activity. The EEG was characterized by high frequency and high amplitude spikes. (c) End of seizure activity. A 3 Hz spike-and-wave pattern was observed towards the end of the seizure. The X-axis shows time (sec), and the Y-axis shows the voltage (μV).
Figure 6.
Figure 6.
EEG recordings showing synchronous spiking activity across three EEG channels at random times (e.g., at 2 and 85 sec. after commencing recording) in a male Fmr1 knockout mouse aged P96 (a) pre-seizure and (b) post-seizure. Green traces are from signals recorded on the skull above the left somatosensory cortex; red are from the right somatosensory cortex; black are from the auditory cortex. The X-axis shows time (sec), and the Y-axis shows the voltage (μV).
Figure 7.
Figure 7.
Spontaneous seizures in adult, Fmr1 KO mice. (a) Baseline EEG from an adult, male Fmr1 knockout mouse that had a spontaneous seizure ~30 min later, shown in (b). EEG during the spontaneous seizure and preictal and postictal phase; this mouse behaved normally for weeks after the seizure, before euthanasia. (c) Baseline Welch plot showing power spectral density. (d) Welch plot during the seizure; note the Y-axis, scale differences between (c) and (d).
Figure 8.
Figure 8.
Spectrograms show temporal power distribution changes for different channels across frequencies for both baseline (a) and seizure (b) recordings.
Picture 1.
Picture 1.
Photo of vivarium during the lights-on cycle. Anti-vibration pads are installed under the rack (center) and cart (bottom right).
Picture 2.
Picture 2.
Photo of an adult (P105), female Fmr1 knockout mouse soon after expiring. Before dying, the mouse was observed by a researcher (JLA) convulsing in its home cage. Suggestive of tonic-clonic seizure, the hindlimbs and toes are extended and flexed, and salivation is evident by the wet fur around the mouth and neck.
See this image and copyright information in PMC

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