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. 2012 Aug;53(8):e161-5.
doi: 10.1111/j.1528-1167.2012.03596.x. Epub 2012 Jul 19.

Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor α1 subunit

Fazal M Arain  1 , Kelli L Boyd, Martin J Gallagher
Affiliations

Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor α1 subunit

Fazal M Arain et al. Epilepsia. 2012 Aug.

Abstract

Autosomal dominant mutations S326fs328X and A322D in the GABA(A) receptor α1 subunit are associated with human absence epilepsy and juvenile myoclonic epilepsy, respectively. Because these mutations substantially reduce α1 subunit protein expression in vitro, it was hypothesized that they produce epilepsy by causing α1 subunit haploinsufficiency. However, in a mixed background strain of mice, α1 subunit deletion does not reduce viability or cause visually apparent seizures; the effects of α1 subunit deletion on electroencephalography (EEG) waveforms were not investigated. Here, we determined the effects of α1 subunit loss on viability, EEG spike-wave discharges and seizures in congenic C57BL/6J and DBA/2J mice. Deletion of α1 subunit caused strain- and sex-dependent reductions in viability. Heterozygous mice experienced EEG discharges and absence-like seizures within both background strains, and exhibited a sex-dependent effect on the discharges and viability in the C57BL/6J strain. These findings suggest that α1 subunit haploinsufficiency can produce epilepsy and may be a major mechanism by which the S326fs328X and A322D mutations cause these epilepsy syndromes.

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Conflict of interest statement

Disclosure of Conflicts of Interest

None of the authors has any conflict of interest to disclose.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1
Figure 1
Gabra1 KO reduces post-P19 survival and body mass. Kaplan-Meier curves illustrate that in both the C57BL/6J (A) and DBA/2J (B) strains, homozygous α1−/− mice (red) had reduced 30 day survival relative to wild type α1+/+ (blue) and heterozygous α1+/− (green) mice. Note that α1−/− mice in the C57BL/6J strain had a higher mortality than those in the DBA/2J strain. The reduced 30 day survival of α1+/− C57BL/6J mice relative to α1+/+ was not statistically significant (P = 0.066). Daily gains in body mass from P7–P30 are presented in panels C–E and the effects of genotype on the final P30 mass are statistically analyzed in panel F. Heterozygous C57BL/6J mice had a sex-dependent reduction in body mass with female (C, F), but not male (E, F) α1+/− having reduced P30 mass; the high mortality of α1−/− C57BL/6J mice precluded quantifying their P30 body mass. Homozygous, but not heterozygous DBA/2J mice had sex-independent reductions in body mass (E, F). * P < 0.05; ns = not significant
Figure 2
Figure 2
Heterozygous KO causes SWD and absence-like seizures. Sample EEG tracings from C57BL/6J (A1, A2) and DBA/2J (B1, B2) α1+/− mice with bipolar (A1, B1) and referential (A2, B2) recordings showing typical SWDs. Referential EEG tracings on an expanded time scale from C7BL/6J (C1) and DBA/2J (C2) mice depict the waveform morphology demonstrating spikes (s), positive transients (pt), and waves (w) similar to those seen in rat models of absence epilepsy. D) Heterozygous C57BL/6J mice had a sex-dependent increase in SWDs with females having two-fold more SWD than males. Heterozygous DBA/2J mice had a sex-independent increase in SWD incidence. Sample EEG (black) and EMG (red) tracing showing attenuation of the EMG signal at the beginning of the SWD and its resumption at its conclusion corresponding to ictal behavioral arrest (E1). The mean normalized EMG spectral power (1–4 Hz) during 83 successive SWD (>2s) was significantly lower than the spectral power for the two seconds preceding and following the SWD(E2). A video EEG demonstrating the behavior arrest and EMG attenuation in three successive SWD is provided in Supplemental Data. F) Ethosuximide (ETX), but not placebo, reduced SWD incidence by 83% compared to baseline EEG. * P < 0.05; ns = not significant
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References

    1. Akman O, Demiralp T, Ates N, Onat FY. Electroencephalographic differences between WAG/Rij and GAERS rat models of absence epilepsy. Epilepsy Res. 2010 May;89(2-3):185–93. - PubMed
    1. Ben-Ari Y, Tyzio R, Nehlig A. Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates. Epilepsia. 2011;52:1544–1558. - PubMed
    1. Chung WK, Shin M, Jaramillo TC, Leibel RL, LeDuc CA, Fischer SG, Tzilianos E, Gheith AA, Lewis AS, Chetkovich DM. Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2. Neurobiol Dis. 2009;33:499–508. - PMC - PubMed
    1. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire JM, Carmant L, Verner A, Lu WY, Wang YT, Rouleau GA. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–189. - PubMed
    1. Ding L, Feng HJ, Macdonald RL, Botzolakis EJ, Hu N, Gallagher MJ. The GABA-A receptor alpha 1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA-A receptors. J Biol Chem. 2010 Aug 20;285(34):26390–405. - PMC - PubMed

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