Peng Z, Huang CS, Stell BM, et al. Altered expression of the delta subunit if the GABA-A 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

ABSTRACT 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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    ABSTRACT: Despite numerous advances, treatment-resistant seizures remain an important problem. Loss of neuronal inhibition is present in a variety of epilepsy models and is suggested as a mechanism for increased excitability, leading to the proposal that grafting inhibitory interneurons into seizure foci might relieve refractory seizures. Indeed, transplanted medial ganglionic eminence interneuron progenitors (MGE-IPs) mature into GABAergic interneurons that increase GABA release onto cortical pyramidal neurons, and this inhibition is associated with reduced seizure activity. An obvious conclusion is that inhibitory coupling between the new interneurons and pyramidal cells underlies this effect. We hypothesized that the primary mechanism for the seizure-limiting effects following MGE-IP transplantation is the tonic conductance that results from activation of extrasynaptic GABA A receptors (GABA A-Rs) expressed on cortical pyramidal cells. Using in vitro and in vivo recording techniques, we demonstrate that GABA A-R α4 subunit deletion abolishes tonic currents (I tonic) in cortical pyramidal cells and leads to a failure of MGE-IP transplantation to attenuate cortical seizure propagation. These observations should influence how the field proceeds with respect to the further development of therapeutic neuronal transplants (and possibly pharmacological treatments).
    Frontiers in Cellular Neuroscience 04/2015; 9(127). DOI:10.3389/fncel.2015.00127 · 4.29 Impact Factor
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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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    ABSTRACT: Extrasynaptic GABAA receptors (GABAARs)-mediated tonic inhibition is reported to involve in the pathogenesis of epilepsy. In this study, we used cyclothiazide (CTZ)-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARs by 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes (PSs) in CA1 pyramidal neurons, and treatment with THIP (5 μmol/L) significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the δ-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation.
    Neuroscience Bulletin 10/2014; 30(5):866-76. DOI:10.1007/s12264-014-1466-8 · 2.51 Impact Factor
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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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    ABSTRACT: The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength.
    Frontiers in Cellular Neuroscience 09/2014; 8:300. DOI:10.3389/fncel.2014.00300 · 4.29 Impact Factor
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