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Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor ?1 subunit.

ABSTRACT: Autosomal dominant mutations S326fs328X and A322D in the GABA(A) receptor ?1 subunit are associated with human absence epilepsy and juvenile myoclonic epilepsy, respectively. Because these mutations substantially reduce ?1 subunit protein expression in vitro, it was hypothesized that they produce epilepsy by causing ?1 subunit haploinsufficiency. However, in a mixed background strain of mice, ?1 subunit deletion does not reduce viability or cause visually apparent seizures; the effects of ?1 subunit deletion on electroencephalography (EEG) waveforms were not investigated. Here, we determined the effects of ?1 subunit loss on viability, EEG spike-wave discharges and seizures in congenic C57BL/6J and DBA/2J mice. Deletion of ?1 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 ?1 subunit haploinsufficiency can produce epilepsy and may be a major mechanism by which the S326fs328X and A322D mutations cause these epilepsy syndromes.

SUBMITTER: Arain FM

PROVIDER: S-EPMC3418418 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Arain Fazal M FM Boyd Kelli L KL Gallagher Martin J MJ

Epilepsia 20120719 8

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 sub ...[more]

PMID: 22812724

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Project description:Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABA(A,fast) and GABA(A,slow). In hippocampal area CA1, GABA(A,fast) is generally believed to underlie gamma oscillations, whereas the contribution of GABA(A,slow) to hippocampal rhythms has been speculative. Hypothesizing that GABA(A) receptors containing the beta(3) subunit contribute to GABA(A,slow) inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABA(A) receptor beta(3) subunit-deficient (beta(3)(-/-)) mice, spontaneous GABA(A,slow) inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABA(A,slow) currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing beta(3) subunits contribute substantially to GABA(A,slow) currents in pyramidal neurons. By contrast, slow inhibitory control of GABA(A,fast)-producing interneurons was unaffected in beta(3)(-/-) mice. In vivo hippocampal network activity was markedly different in the two genotypes. In beta(3)(-/-) mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency ("nesting") was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of beta(3) subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABA(A,fast) -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

Dataset Information

Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor ?1 subunit.

Publications

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

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