Cornichons Control ER Export of AMPA Receptors to Regulate Synaptic Excitability

Brockie, Penelope J.; Jensen, Michael; Mellem, Jerry E.; Jensen, Erica; Yamasaki, Tokiwa; Wang, Rui; Maxfield, Dane; Thacker, Colin; Hoerndli, Frédéric; Dunn, Patrick; Tomita, Susumu; Madsen, David M.; Maricq, Andres V.

doi:10.1016/j.neuron.2013.07.028

Cited by 49 publications

(50 citation statements)

References 58 publications

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“…Moreover, TARPs are essential for ER export of correctly assembled receptors 85 and remain part of the AMPAR complex throughout Golgi processing and forward trafficking to eventual surface expression at the postsynaptic density 86 . Similarly, cornichons have a welldefined role in the export of specific proteins from the ER 87,88 including AMPARs 89,90 .…”

Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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“…The subunit composition determines their kinetics and pharmacological properties (4)(5)(6). Except for these pore-forming subunits, native AMPARs are thought to be macromolecular complexes associated with a variety of auxiliary proteins, including transmembrane AMPA receptor regulatory proteins, cornichons, Gsg1l, syndig1, and CKAMP44 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Recently, a high-resolution proteomics analysis revealed 21 additional proteins associated with native AMPAR core subunits (21).…”

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confidence: 99%

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Wei

Zhang

Jia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.ABHD6 | AMPA receptor | synapses | receptor trafficking

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“…For example, in cornichon knockout mice, AMPAR synaptic transmission is reduced in the hippocampus due in part to alteration in AMPAR surface expression (Herring et al 2013). Consistent with this, C. elegans cornichon mutants exhibit larger glutamate currents and an increase in AMPAR number (Brockie et al 2013). …”

Section: Discussionmentioning

confidence: 80%

“…In the CNS, a proteomic screen has revealed that two vertebrate homologs of cornichon (CNIH2 and CNIH3) can serve as auxiliary subunits of AMPA receptors (Schwenk et al 2009). While the physiological functions of vertebrate cornichons are complex (e.g., Kato et al 2010;Herring et al 2013), in invertebrate models cornichon is proposed to limit the exportation of GLR-1 receptors from the endoplasmic reticulum to the cell surface (Brockie et al 2013). Specifically, overexpression of cornichon in C. elegans decreases synaptic expression of GLR-1 receptors and reduces evoked glutamate currents; loss-offunction mutants exhibit the opposite phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of a whole-body form of long-term habituation inAplysia californica

et al. 2014

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Habituation is the simplest form of learning, but we know little about the transcriptional mechanisms that encode long-term habituation memory. A key obstacle is that habituation is relatively stimulus-specific and is thus encoded in small sets of neurons, providing poor signal/noise ratios for transcriptional analysis. To overcome this obstacle, we have developed a protocol for producing whole-body long-term habituation of the siphon-withdrawal reflex (SWR) of Aplysia californica. Specifically, we constructed a computer-controlled brushing apparatus to apply low-intensity tactile stimulation over the entire dorsal surface of Aplysia at regular intervals. We found that 3 d of training (10 rounds of stimulation/day; each round ¼ 15 min brushing at a 10-sec ISI; 15-min rest between rounds) produces habituation with several characteristics favorable for mechanistic investigation. First, habituation is widespread, with SWR durations reduced whether the reflex is evoked by tactile stimulation to the head, tail, or the siphon. Second, long-term habituation is sensitive to the pattern of training, occurring only when brushing sessions are spaced out over 3 d rather than massed into a single session. Using a custom-designed microarray and quantitative PCR, we show that long-term habituation produces long-term up-regulation of an apparent Aplysia homolog of cornichon, a protein important for glutamate receptor trafficking. Our training paradigm provides a promising starting point for characterizing the transcriptional mechanisms of long-term habituation memory.

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Cornichons Control ER Export of AMPA Receptors to Regulate Synaptic Excitability

Cited by 49 publications

References 58 publications

Synaptic AMPA receptor composition in development, plasticity and disease

Synaptic AMPA receptor composition in development, plasticity and disease

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Transcriptional analysis of a whole-body form of long-term habituation inAplysia californica

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