Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy

Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095-1763, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2004; 24(39):8629-39. DOI: 10.1523/JNEUROSCI.2877-04.2004
Source: PubMed


delta Subunit-containing GABA(A) receptors are located predominantly at nonsynaptic sites in the dentate gyrus where they may play important roles in controlling neuronal excitability through tonic inhibition and responses to GABA spillover. Immunohistochemical methods were used to determine whether delta subunit expression was altered after pilocarpine-induced status epilepticus in C57BL/6 mice in ways that could increase excitability of the dentate gyrus. In pilocarpine-treated animals, the normal diffuse labeling of the delta subunit in the dentate molecular layer was decreased by 4 d after status epilepticus (latent period) and remained low throughout the period of chronic seizures. In contrast, diffuse labeling of alpha4 and gamma2 subunits, potentially interrelated GABA(A) receptor subunits, was increased during the chronic period. Interestingly, delta subunit labeling of many interneurons progressively increased after pilocarpine treatment. Consistent with the observed changes in delta subunit labeling, physiological studies revealed increased excitability in the dentate gyrus of slices obtained from the pilocarpine-treated mice and demonstrated that physiological concentrations of the neurosteroid tetrahydrodeoxycorticosterone were less effective in reducing excitability in the pilocarpine-treated animals than in controls. The findings support the idea that alterations in nonsynaptic delta subunit-containing GABA(A) receptors in both principal cells and interneurons could contribute to increased seizure susceptibility in the hippocampal formation in a temporal lobe epilepsy model.

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    • " is associated with a decrease in α4 expression ( Peng et al . , 2002 ) and has pro - convulsant effects ( Spigelman et al . , 2002 ) . In dentate gyrus cells in a rat TLE model , there was a significant decrease in the neurosteroid - sensitive tonic current which occurred in combination with a decrease in the surface expression of the δ subunit ( Peng et al . , 2004 ; Rajasekaran et al . , 2010 ) , suggesting a close relationship between extrasynaptic GABA A - Rs and seizure activity . In a parallel fashion , there is a shift in α4 expression from the extrasynaptic to synaptic membrane in the rat TLE model ( Sun et al . , 2007 ) , consistent with a loss of extrasynaptic GABA A - Rs . In a rat trauma"
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    • "The role of synaptic GABAR-mediated phasic inhibition in epileptogenesis has been well investigated [10] [11] , yet recent research efforts have also revealed that extrasynaptic GABA A R-mediated tonic inhibition plays an equivalent or even more critical role in the regulation of epilepsy [12] [13] . Moreover, clinical studies have shown that there is a significant down-regulation of δ-subunitcontaining GABA A Rs in brain samples from patients with temporal lobe epilepsy [14] , and that mutation of the δ-subunit is one of the pathogenic mechanisms of epilepsy [15] . "
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    • "Gene expression and mRNA translation of receptor subunits can further modulate the surface availability and synaptic accumulation of neurotransmitter receptors during synaptic plasticity (Mameli et al., 2007; Jung et al., 2014). For instance, the upregulation of GABAARs and gephyrin proteins contributes to iLTP expression, while their downregulation has been observed during status epilepticus in the CA1 region of the hippocampus (Peng et al., 2004; González et al., 2013; Petrini et al., 2014). Moreover, it has been reported that fear conditioning regulates the gene expression of gephyrin in the amygdala (Ressler et al., 2002; Chhatwal et al., 2005). "
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