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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    • "This process appears to play a crucial role in limiting endocytosis of AMPAR to adjust the level of AMPAR at the synaptic membrane. Thus, ATAD1 controls the endocytosis and removal of AMPAR from the postsynaptic membrane and thereby regulates synaptic plasticity and learning and memory [57]. First hints that Msp1p/ATAD1 may also play a role for peroxisomes came from proteomic studies on mouse kidney peroxisomes. "
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    Biochimica et Biophysica Acta 10/2015; DOI:10.1016/j.bbamcr.2015.10.001 · 4.66 Impact Factor
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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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