The AAA+ ATPase Thorase regulates AMPA receptor-dependent synaptic plasticity and behavior

Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell (Impact Factor: 32.24). 04/2011; 145(2):284-99. DOI: 10.1016/j.cell.2011.03.016
Source: PubMed


The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory.

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Available from: Ho Chul Kang, Dec 29, 2013
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    • "NSF binds to AMPA receptor GluR2, disassembles the GluR2-PICK1 complex in postsynaptic neurons, and regulates long-term synaptic plasticity [48]. Similarly, AAA+ ATPase Thorase mediates the internalization of AMPA receptors by disassembling the AMPA receptor-GRIP1 complex and regulates AMPA receptor-dependent long-term synaptic plasticity [49]. The present results suggest that torsinA, a member of AAA+ ATPase family, may directly regulate action potential-dependent neurotransmitter release similar to NSF. "
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    ABSTRACT: DYT1 early-onset generalized torsion dystonia (DYT1 dystonia) is an inherited movement disorder caused by mutations in one allele of DYT1 (TOR1A), coding for torsinA. The most common mutation is a trinucleotide deletion (ΔGAG), which causes a deletion of a glutamic acid residue (ΔE) in the C-terminal region of torsinA. Although recent studies using cultured cells suggest that torsinA contributes to protein processing in the secretory pathway, endocytosis, and the stability of synaptic proteins, the nature of how this mutation affects synaptic transmission remains unclear. We previously reported that theta-burst-induced long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not altered in Dyt1 ΔGAG heterozygous knock-in (KI) mice. Here, we examined short-term synaptic plasticity and synaptic transmission in the hippocampal slices. Field recordings in the hippocampal Schaffer collaterals (SC) pathway revealed significantly enhanced paired pulse ratios (PPRs) in Dyt1 ΔGAG heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell recordings from the CA1 neurons showed that Dyt1 ΔGAG heterozygous KI mice exhibited normal miniature excitatory post-synaptic currents (mEPSC), suggesting that action-potential independent spontaneous pre-synaptic release was normal. On the other hand, there was a significant decrease in the frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents (sEPSC) in Dyt1 ΔGAG heterozygous KI mice, suggesting that the action-potential dependent pre-synaptic release was impaired. Moreover, hippocampal torsinA was significantly reduced in Dyt1 ΔGAG heterozygous KI mice. Although the hippocampal slice model may not represent the neurons directly associated with dystonic symptoms, impaired release of neurotransmitters caused by partial dysfunction of torsinA in other brain regions may contribute to the pathophysiology of DYT1 dystonia.
    PLoS ONE 08/2013; 8(8):e72491. DOI:10.1371/journal.pone.0072491 · 3.23 Impact Factor
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    • "To label surface proteins, a cross-linking reagent, bis(sulfosuccinimidyl ) suberate (BS 3 ; Thermo Fisher Scientific) was used as described in previous studies [4] [57] with some modifications. After perfusion of mice via the heart with cold ACSF, the L4/5 regions of the spinal cord were removed 70 minutes after NMDA injection, and placed into cold ACSF oxygenated with mixed gas (95% O 2 and 5% CO 2 ). "
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    ABSTRACT: Sensitization of dorsal horn neurons (DHNs) in the spinal cord is dependent on pain-related synaptic plasticity and causes persistent pain. The DHN sensitization is mediated by a signal transduction pathway initiated by the activation of N-methyl-d-aspartate receptors (NMDA-Rs). Recent studies have shown that elevated levels of reactive oxygen species (ROS) and phosphorylation-dependent trafficking of GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) are a part of the signaling pathway for DHN sensitization. However, the relationship between ROS and AMPA-R phosphorylation and trafficking is not known. Thus, this study investigated the effects of ROS scavengers on the phosphorylation and cell-surface localization of GluA1 and GluA2. Intrathecal NMDA- and intradermal capsaicin-induced hyperalgesic mice were used for this study since both pain models share the NMDA-R activation-dependent DHN sensitization in the spinal cord. Our behavioral, biochemical, and immunohistochemical analyses demonstrated that: 1) NMDA-R activation in vivo increased the phosphorylation of AMPA-Rs at GluA1 (S818, S831, and S845) and GluA2 (S880) subunits; 2) NMDA-R activation in vivo increased cell-surface localization of GluA1 but decreased that of GluA2; and 3) reduction of ROS levels by ROS scavengers PBN (N-tert-butyl-α-phenylnitrone) or TEMPOL (4-hydroxy-2, 2, 6, 6-tetramethylpiperidin-1-oxyl) reversed these changes in AMPA-Rs, as well as pain-related behavior. Given that AMPA-R trafficking to the cell surface and synapse is regulated by NMDA-R activation-dependent phosphorylation of GluA1 and GluA2, our study suggests that the ROS-dependent changes in the phosphorylation and cell-surface localization of AMPA-Rs are necessary for DHN sensitization and thus, pain-related behavior. We further suggest that ROS reduction will ameliorate these molecular changes and pain.
    Pain 07/2012; 153(9):1905-15. DOI:10.1016/j.pain.2012.06.001 · 5.21 Impact Factor
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    • "GluR2/3 is maintained at the postsynaptic membrane mainly due to the GluR2 C-end binding to ABP/GRIP (PSD adapter proteins). However, the complex between the GluR2 C-end/palmitoylated GRIP is not permanent and AAA+ ATPase Thorase is able to disassemble the AMPAR-GRIP1 complex and induce AMPAR endocytosis and LTD [146]. One of ways of maintaining GluR2/3 AMPAR at the postsynaptic membrane is to continuously remove its subunits from endosomes and increase their residence time at the postsynaptic membrane [135]. "
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    ABSTRACT: Signal transmission from the human retina to visual cortex and connectivity of visual brain areas are relatively well understood. How specific visual perceptions transform into corresponding long-term memories remains unknown. Here, I will review recent Blood Oxygenation Level-Dependent functional Magnetic Resonance Imaging (BOLD fMRI) in humans together with molecular biology studies (animal models) aiming to understand how the retinal image gets transformed into so-called visual (retinotropic) maps. The broken object paradigm has been chosen in order to illustrate the complexity of multisensory perception of simple objects subject to visual—rather than semantic—type of memory encoding. The author explores how amygdala projections to the visual cortex affect the memory formation and proposes the choice of experimental techniques needed to explain our massive visual memory capacity. Maintenance of the visual long-term memories is suggested to require recycling of GluR2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and β 2 -adrenoreceptors at the postsynaptic membrane, which critically depends on the catalytic activity of the N-ethylmaleimide-sensitive factor (NSF) and protein kinase PKMζ.
    Neural Plasticity 05/2012; 14(Article ID 392695). DOI:10.1155/2012/392695 · 3.58 Impact Factor
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