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. Author manuscript; available in PMC: 2011 Feb 8.
Published in final edited form as: Epilepsia. 2007;48(Suppl 8):11–13. doi: 10.1111/j.1528-1167.2007.01336.x

Changes in GABAA receptors in status epilepticus

Guenther Sperk 1
PMCID: PMC3034838  EMSID: UKMS33748  PMID: 18329986

GABA (γ -aminobutyric acid) is the principal inhibitory neurotransmitter in the mammalian brain. Its fast inhibitory actions are mediated by GABAA receptors representing ligand-operated chloride channels. GABAA receptors consist of 5 subunits generally belonging to different subunit classes (Macdonald and Olsen, 1994). Molecular cloning of complementary DNA encoding GABAA receptors in humans identified 8 different subunit classes with at least 20 different subunits (six α, four β, three γ, one δ, one ε, one π, one θ, three ρ; Barnard et al., 1998). Each of these subunits exhibits a specific regional, cellular, and subcellular distribution in the brain (Wisden et al., 1992; Fritschy and Mohler, 1995; Sperk et al., 1997) that is partially overlapping with that of other subunits, indicating formation of a large number of different GABAA receptor subtypes with distinct subunit composition (For review, see Sieghart and Sperk, 2002). GABAA receptors are the site of action of several antiepileptic drugs (Olsen and Avoli, 1997), and depending on their subunit composition, exhibit distinct pharmacological and electrophysiological properties (Sieghart and Sperk, 2002). Most GABAA receptors consist of two α-, two β-, and one γ - (mostly γ 2) or one δ-subunit. Actions of GABA are primarily mediated by a β-subunits within the receptor, those of benzodiazepines by an α-subunit, involving however also interactions with the other subunits (β and γ 2).

Reduced GABA-ergic function resulting from reduced GABA synthesis (Freichel et al., 2006), reduced reuptake (Chiu et al., 2005), mutations of GABAA receptor subunits (e.g., subunits α1, β3, or γ 2; DeLorey et al., 1998; Baulac et al., 2001; Cossette et al., 2002), or altered function of chloride transporters building the chloride ion gradient (Haug et al., 2003) cause epilepsies in humans and experimental animals. On the other hand, it has been suggested that status epilepticus or subsequent epileptogenesis may induce altered expression of individual GABAA receptor subunits and modified assembly of GABAA receptors. Hypthetically, this could result in altered GABA ergic transmission possibly contributing to increased seizure susceptibility or reduced sensitivity of drugs acting by enhancing GABAergic transmission.

GABAA Receptor Subunits in Animal Models of Status Epilepticus

Dentate gyrus

Changes in GABAA receptor subunits were thoroughly investigated after status epilepticus in rats induced by kainic acid (Schwarzer et al., 1997; Tsunashima et al., 1997), pilocarpine (Brooks-Kayal et al., 1998) or by electrical stimulation (Nishimura et al., 2005), and in the pilocarpine model of the mouse (Houser & Esclapez, 2003; Peng et al., 2004) (Table 1). Due to the lack in neurode-generation in the granule cell layer, changes in GABAA receptors can be there most unambiguously judged. Similar changes in the expression of GABAA receptor subunits were observed in the different models when examined in brain tissue after the status, but differed when examined in granule cells cultured from epileptic tissue (Brooks-Kayal et al., 1998).

Table 1.

Changes in the expression of GABAA receptor subunits in animal models of status epilepticus

Kainic acid-induced
status epilepticus
 Electrically induced
status epilepticus
12 h 7–30 d 30 d
(IR)
(Schwarzer et al., 1997)		 24 h 7–30 d
(mRNA)
(Tsunashima et al., 1997)		 (mRNA)
(Nishimura et al., 2005)
α 1 ++ + ++ ++ +
α 2 − = ++ (−) (+)
α 3 − (+) = nd nd
α 4 + (+) + + ++
α 5 − − − ± − (−)
β 1 + + ± + +
β 2 ± ++ ++ ++ ++
β 3 (−) (+) ++ + (+)
γ 2 (−) = + (+) (+)
δ − − − − − −
Open in a new tab

++, > 150%; +, >115–150%; (+) 105–115%; = , 96–104; (−), 91–95%; −, 50–80%; − −, <50% of controls.

Shaded values indicate statistical significance at p < 0.05 level or higher. nd, not determined.

One of the most consistent findings is a fast and lasting decrease in the expression of the δ-subunit in all status models (Schwarzer et al., 1997; Tsunashima et al., 1997; Peng et al., 2004). This indicates a shift from receptors containing a γ 2-subunit to receptors containing a δ-subunit, resulting in an overall reduction of tonic inhibition mediated by δ-subunit containing extra-synaptic receptors in granule cells (Peng et al., 2004). In all status models, a tendency for increases in α1-subunit mRNA and protein was observed. Similarly, lasting increases in α4 mRNA levels were observed in granule cells in the kainate and SE models (Tsunashima et al., 1997; Nishimura et al., 2005), accompanied by decreased expression of the α5-subunit (Tsunashima et al., 1997; Houser & Esclapez, 2003; Nishimura et al., 2005).

Expression of all GABAA receptor β-subunits (notably that of β2 and β3) tends to increase in animal all status models at mRNA and protein levels (Schwarzer et al., 1997; Nusser et al., 1998; Lauren et al., 2003; Nishimura et al., 2005). The β-subunits carry the recognition site for GABA. Their upregulation could be associated with augmented GABA-ergic transmission (Nusser et al., 1998). Subunit γ 2 mRNA levels (as those of α2) are transiently decreased in granule cells in the kainate model at the early intervals after the status epilepticus (Tsunashima et al., 1997), but increase both at mRNA and protein levels at later intervals after the initial status epilepticus induced by kainic acid injection or electrical stimulation (Schwarzer et al., 1997; Nishimura et al., 2005) and in the mouse pilocarpine model (Peng et al., 2004). Similarly, increases in γ 2-immunoreactivity were observed in dendrites of CA1 and CA3 pyramidal cells (Schwarzer et al., 1997).

Pyramidal cell layer

Due to variable degrees of neurodegeneration in the Ammon’s horn, results obtained for pyramidal cells are more difficult to interpret than those for granule cells. Some of the decreases in GABAA receptor subunits (α2, α5, β3, γ 2, but also β1 and β2) occur rather fast and could precede neurodegeneration. In the chronic state, some changes indicate compensatory increases in expression of certain subunits (notably subunits α2 and β3 in sector CA3; Tsunashima et al., 1997). On the protein level, considerable reductions related to neuronal cell death were seen in most subunits in both sectors CA1 and CA3. Interestingly, also immunoreactivities for subunits α2 and γ 2 appear to be somewhat preserved in sector CA3 at the late interval 30 days after kainate-induced seizures (Schwarzer et al., 1997).

In conclusion, there are considerable changes in the expression patterns of GABAA receptor subunits after status epilepticus indicating markedly altered GABAergic transmission. These changes may have relevance for epileptogenesis induced by status epilepticus and for resistency of drugs acting through the GABAergic system.

Acknowledgments

The work was supported by the Austrian Science Fund and by the EC contract number LSH-CT-2006-037315 (EPICURE) FP6 – Thematic priority LIFESCIHEALTH.

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