Sustained Structural Change of GABAA Receptor-Associated Protein Underlies Long-Term Potentiation at Inhibitory Synapses on a Cerebellar Purkinje Neuron
Abstract:Fast inhibitory synaptic transmission is predominantly mediated by GABA A receptor (GABA A R) in the CNS. Although several types of neuronal activity-dependent plasticity at GABAergic synapses have been reported, the detailed mechanism is elusive. Here we show that binding of structurally altered GABA A R-associated protein (GABARAP) to GABA A R ␥2 subunit and to tubulin is critical for long-term potentiation [called rebound potentiation (RP)] at inhibitory synapses on a cerebellar Purkinje neuron (PN). Either… Show more
“…Although a scrambled control peptide had no effect on the NMDA-mediated increase in GABA A R surface expression (48.9 Ϯ 9.18% increase from control; n ϭ 5; p Ͻ 0.05), when cells were pretreated with the GABARAP inhibitory peptide for 30 min, NMDA induced a significant decrease in GABA A R surface levels (Ϫ38.17 Ϯ 5.15%; n ϭ 5; p Ͻ 0.05). As reported previously (Kawaguchi and Hirano, 2007), disruption of the GABARAP-GABA A R interaction with the GABARAP inhibitory peptide had no effect on basal surface GABA A R expression (1.42 Ϯ 13.03% change from control; n ϭ 5; p Ͼ 0.1).…”
Section: Gabarap Is Central To Gaba a Receptor Insertion After Chem-ltdsupporting
confidence: 77%
“…Interestingly, it is not clear that expression of RP, although similar to the NMDAR-dependent potentiation described here, is caused by trafficking of GABA A Rs to synapses. In fact, Kawaguchi and Hirano (2007) reported no change in surface GABA A R expression after RP induction. It remains possible that GABARAP has multiple functions in regulating GABAergic signaling: through altered GABA A R function as seen in Purkinje neurons and through enhanced GABA A R numbers as we found in the hippocampus.…”
Section: Discussionmentioning
confidence: 96%
“…Kawaguchi and Hirano (2007) showed that the interaction of GABARAP with the ␥2 subunit of the GABA A R is necessary for rebound potentiation (RP), a form of inhibitory synaptic potentiation that occurs in cerebellar Purkinje neurons after postsynaptic depolarization (Kano et al, 1992). RP was found to require a structural change in GABARAP mediated by CaMKII activity (Kawaguchi and Hirano, 2007).…”
The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA A receptors (GABA A Rs) are also subject to regulation and that GABA A R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases
“…Although a scrambled control peptide had no effect on the NMDA-mediated increase in GABA A R surface expression (48.9 Ϯ 9.18% increase from control; n ϭ 5; p Ͻ 0.05), when cells were pretreated with the GABARAP inhibitory peptide for 30 min, NMDA induced a significant decrease in GABA A R surface levels (Ϫ38.17 Ϯ 5.15%; n ϭ 5; p Ͻ 0.05). As reported previously (Kawaguchi and Hirano, 2007), disruption of the GABARAP-GABA A R interaction with the GABARAP inhibitory peptide had no effect on basal surface GABA A R expression (1.42 Ϯ 13.03% change from control; n ϭ 5; p Ͼ 0.1).…”
Section: Gabarap Is Central To Gaba a Receptor Insertion After Chem-ltdsupporting
confidence: 77%
“…Interestingly, it is not clear that expression of RP, although similar to the NMDAR-dependent potentiation described here, is caused by trafficking of GABA A Rs to synapses. In fact, Kawaguchi and Hirano (2007) reported no change in surface GABA A R expression after RP induction. It remains possible that GABARAP has multiple functions in regulating GABAergic signaling: through altered GABA A R function as seen in Purkinje neurons and through enhanced GABA A R numbers as we found in the hippocampus.…”
Section: Discussionmentioning
confidence: 96%
“…Kawaguchi and Hirano (2007) showed that the interaction of GABARAP with the ␥2 subunit of the GABA A R is necessary for rebound potentiation (RP), a form of inhibitory synaptic potentiation that occurs in cerebellar Purkinje neurons after postsynaptic depolarization (Kano et al, 1992). RP was found to require a structural change in GABARAP mediated by CaMKII activity (Kawaguchi and Hirano, 2007).…”
The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA A receptors (GABA A Rs) are also subject to regulation and that GABA A R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases
“…This “rebound potentiation” (RP) occurs through activation of voltage-gated Ca 2+ channels (VGCCs) resulting in a transient Ca 2+ influx and is dependent upon CamKII (Kano, Kano, Fukunaga, & Konnerth, 1996) and γ2 subunit association with GABARAP (Kawaguchi & Hirano, 2007). Further, RP can be suppressed by GABA type B receptor (GABA B R) activation through decreasing levels of PKA.…”
Section: Signaling Pathways That Modulate Gabaar Phosphorylationmentioning
γ-Aminobutyric acid type A receptors (GABAARs) are the principal mediators of fast synaptic inhibition in the brain as well as the low persistent extrasynaptic inhibition, both of which are fundamental to proper brain function. Thus unsurprisingly, deficits in GABAARs are implicated in a number of neurological disorders and diseases. The complexity of GABAAR regulation is determined not only by the heterogeneity of these receptors but also by its posttranslational modifications, the foremost, and best characterized of which is phosphorylation. This review will explore the details of this dynamic process, our understanding of which has barely scratched the surface. GABAARs are regulated by a number of kinases and phosphatases, and its phosphorylation plays an important role in governing its trafficking, expression, and interaction partners. Here, we summarize the progress in understanding the role phosphorylation plays in the regulation of GABAARs. This includes how phosphorylation can affect the allosteric modulation of GABAARs, as well as signaling pathways that affect GABAAR phosphorylation. Finally, we discuss the dysregulation of GABAAR phosphorylation and its implication in disease processes.
“…Molecular regulation mechanisms of RP induction has been studied extensively [13], and it was revealed that interaction of GABA A receptor binding protein (GABARAP) and GABA A receptor is necessary for RP induction [16]. This result prompted us to examine physiological roles of RP using RP-deficient mice.…”
Long-term depression (LTD) at excitatory synapses between parallel fibers and a Purkinje cell has been regarded as a critical cellular mechanism for motor learning. However, it was demonstrated that normal motor learning occurs under LTD suppression, suggesting that cerebellar plasticity mechanisms other than LTD also contribute to motor learning. One candidate for such plasticity is rebound potentiation (RP), which is long-term potentiation at inhibitory synapses between a stellate cell and a Purkinje cell. Both LTD and RP are induced by the increase in postsynaptic Ca(2+) concentration, and work to suppress the activity of a Purkinje cell. Thus, LTD and RP might work synergistically, and one might compensate defects of the other. RP induction is dependent on the interaction between GABAA receptor and GABAA receptor binding protein (GABARAP). Transgenic mice expressing a peptide which inhibits binding of GABARAP and GABAA receptor only in Purkinje cells show defects in both RP and adaptation of vestibulo-ocular reflex (VOR), a motor learning paradigm. However, another example of motor learning, adaptation of optokinetic response (OKR), is normal in the transgenic mice. Both VOR and OKR are reflex eye movements suppressing the slip of visual image on the retina during head movement. Previously, we reported that delphilin knockout mice show facilitated LTD induction and enhanced OKR adaptation, but we recently found that VOR adaptation was not enhanced in the knockout mice. These results together suggest that animals might use LTD and RP differently depending on motor learning tasks.
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