Alpha subunit-dependent glycine receptor clustering and regulation of synaptic receptor numbers

Patrizio, Angela; Renner, Marianne; Pizzarelli, Rocco; Triller, Antoine; Specht, Christian G.

doi:10.1038/s41598-017-11264-3

Cited by 54 publications

(87 citation statements)

References 46 publications

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“…Using immunocytochemistry, previous work indicated that approximately half of lamina II neurons appear to co-express both subunits, and our data in the GAD-65 cell population are consistent with these results (Harvey et al, 2004). Recent work in cultured neurons indicates that IL-1β does not affect GlyRα3-containing receptors, although IL-1β potentiation of GlyRα1- containng receptors was not observed in this study (Patrizio et al, 2017).…”

Section: Discussioncontrasting

confidence: 83%

NMDA receptor activation induces long-term potentiation of glycine synapses

Kloc

Pradier

Chirila

et al. 2019

Preprint

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Of the fast ionotropic synapses, glycinergic synapses are the least well understood, but are vital for the maintenance of inhibitory signaling in the brain and spinal cord. Glycinergic signaling comprises half of the inhibitory signaling in the spinal cord, and glycinergic synapses are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we have investigated the rapid and prolonged potentiation of glycinergic synapses in the superficial dorsal horn of young male and female mice after brief activation of NMDA receptors (NMDARs). Glycinergic inhibitory postsynaptic currents (IPSCs) evoked with lamina II-III stimulation in identified GABAergic neurons in lamina II were potentiated by bath-applied Zn 2+ and were depressed by the prostaglandin PGE2, consistent with the presence of both GlyRα1-and GlyRα3-containing receptors. NMDA application rapidly potentiated synaptic glycinergic currents. Whole-cell currents evoked by exogenous glycine were also rapidly potentiated by NMDA, indicating that the potentiation results from altered numbers or conductance of postsynaptic glycine receptors. Repetitive depolarization alone of the postsynaptic GABAergic neuron also potentiated glycinergic synapses, and intracellular EGTA prevented both NMDA-induced and depolarization-induced potentiation of glycinergic IPSCs. Driving trpv1 lineage afferents optogenetically also triggered NMDAR-dependent potentiation of glycinergic synapses. Our results suggest that during peripheral injury or inflammation, nociceptor firing during injury is likely to potentiate glycinergic synapses on GABAergic neurons. This disinhibition mechanism may be engaged rapidly, altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain. Significance:Of the fast ionotropic synapses, glycinergic synapses are the least well understood, yet glycinergic synapses comprise half of the inhibition in the spinal cord, and are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we report that bath applied NMDA, repetitive postsynaptic depolarization, or optogenetic activation of primary nociceptor afferents all produce LTP at superficial dorsal horn synapses. During peripheral injury or inflammation, nociceptor firing is likely to engage this mechanism in inhibitory neurons, rapidly altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain.

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Section: Discussioncontrasting

confidence: 83%

NMDA receptor activation induces long-term potentiation of glycine synapses

Kloc

Pradier

Chirila

et al. 2019

Preprint

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“…For instance, quantitative 3D-PALM analysis has revealed the gephyrin organization in inhibitory synapses in cultured spinal cord neurons: the ensuring calculations estimated the postsynaptic clusters of 40–500 gephyrin molecules, packed at a density of about 5000 molecules/μm 2 , whereas synapses in situ contained about three times as many molecules and were packed more densely (Specht et al, 2013 ). The same group recently used quantitative PALM to show that alpha-1 and alpha-3 containing glycine receptors display the same α 3 :β 2 stoichiometry and gephyrin binding (Patrizio et al, 2017 ). However, the authors found that alpha-1 containing receptors are more mobile and less densely packed (1100 molecules/μm 2 vs. 1500 molecules/μm 2 ; alpha-3 containing receptors) and that their number at synapses was reduced in response to interleukin 1β.…”

Section: Sr Imaging Of the Postsynaptic Sitementioning

confidence: 99%

The Nanoworld of the Tripartite Synapse: Insights from Super-Resolution Microscopy

Heller

Rusakov

2017

Front. Cell. Neurosci.

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Synaptic connections between individual nerve cells are fundamental to the process of information transfer and storage in the brain. Over the past decades a third key partner of the synaptic machinery has been unveiled: ultrathin processes of electrically passive astroglia which often surround pre- and postsynaptic structures. The recent advent of super-resolution (SR) microscopy has begun to uncover the dynamic nanoworld of synapses and their astroglial environment. Here we overview and discuss the current progress in our understanding of the synaptic nanoenvironment, as gleaned from the imaging methods that go beyond the diffraction limit of conventional light microscopy. We argue that such methods are essential to achieve a new level of comprehension pertinent to the principles of signal integration in the brain.

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“…The PSD has mostly been studied in glutamatergic neurons, where AMPA and NMDA ionotropic receptors are clustered, proximal to the pre-synaptic AZ sites (Boeckers, 2006;Chen et al, 2015;Tang et al, 2016;Scheefhals and MacGillavry, 2018). Ionotropic glycine receptor clustering was also reported in the membrane of the postsynaptic cell (Patrizio et al, 2017;Schaefer et al, 2018). Such clusters are found in motor neuronal membranes of the adult spinal cord, brain stem, and retina, and were shown to be essential for proper neuron hyperpolarization.…”

Section: Site-specific Clustering Of Ion Channels Affects Signal Genementioning

confidence: 99%

“…Such clusters are found in motor neuronal membranes of the adult spinal cord, brain stem, and retina, and were shown to be essential for proper neuron hyperpolarization. Impaired clustering of glycine receptors is associated with startle disease in mice (Patrizio et al, 2017;Schaefer et al, 2018). The clustering of different ion channels and receptors in proximity to other intracellular signaling and cytoskeletal structural proteins at the PSD is also essential for ensuring a robust response to neurotransmitter binding and for modulating the evoked synaptic potential, whether inhibitory or excitatory, of the post-synaptic cell membrane (Boeckers, 2006).…”

Section: Site-specific Clustering Of Ion Channels Affects Signal Genementioning

confidence: 99%

Bridging the Molecular-Cellular Gap in Understanding Ion Channel Clustering

Nirenberg

Yifrach

2020

Front. Pharmacol.

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The clustering of many voltage-dependent ion channel molecules at unique neuronal membrane sites such as axon initial segments, nodes of Ranvier, or the post-synaptic density, is an active process mediated by the interaction of ion channels with scaffold proteins and is of immense importance for electrical signaling. Growing evidence indicates that the density of ion channels at such membrane sites may affect action potential conduction properties and synaptic transmission. However, despite the emerging importance of ion channel density for electrical signaling, how ion channel-scaffold protein molecular interactions lead to cellular ion channel clustering, and how this process is regulated are largely unknown. In this review, we emphasize that voltagedependent ion channel density at native clustering sites not only affects the density of ionic current fluxes but may also affect the conduction properties of the channel and/or the physical properties of the membrane at such locations, all changes that are expected to affect action potential conduction properties. Using the concrete example of the prototypical Shaker voltage-activated potassium channel (Kv) protein, we demonstrate how insight into the regulation of cellular ion channel clustering can be obtained when the molecular mechanism of ion channel-scaffold protein interaction is known. Our review emphasizes that such mechanistic knowledge is essential, and when combined with super-resolution imaging microscopy, can serve to bridge the molecular-cellular gap in understanding the regulation of ion channel clustering. Pressing questions, challenges and future directions in addressing ion channel clustering and its regulation are discussed.

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Alpha subunit-dependent glycine receptor clustering and regulation of synaptic receptor numbers

Cited by 54 publications

References 46 publications

NMDA receptor activation induces long-term potentiation of glycine synapses

NMDA receptor activation induces long-term potentiation of glycine synapses

The Nanoworld of the Tripartite Synapse: Insights from Super-Resolution Microscopy

Bridging the Molecular-Cellular Gap in Understanding Ion Channel Clustering

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