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Ryanodine Receptor Activation Induces Long-Term Plasticity of Spine Calcium Dynamics.

Johenning FW, Theis AK, Pannasch U, Rückl M, Rüdiger S, Schmitz D - PLoS Biol. (2015)

Bottom Line: Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger.We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines.Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Center, Charité-Universitätsmedizin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.

ABSTRACT
A key feature of signalling in dendritic spines is the synapse-specific transduction of short electrical signals into biochemical responses. Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger. Upon action potential firing, the majority of spines are subject to global back-propagating action potential (bAP) Ca2+ transients. These transients translate neuronal suprathreshold activation into intracellular biochemical events. Using a combination of electrophysiology, two-photon Ca2+ imaging, and modelling, we demonstrate that bAPs are electrochemically coupled to Ca2+ release from intracellular stores via ryanodine receptors (RyRs). We describe a new function mediated by spine RyRs: the activity-dependent long-term enhancement of the bAP-Ca2+ transient. Spines regulate bAP Ca2+ influx independent of each other, as bAP-Ca2+ transient enhancement is compartmentalized and independent of the dendritic Ca2+ transient. Furthermore, this functional state change depends exclusively on bAPs travelling antidromically into dendrites and spines. Induction, but not expression, of bAP-Ca2+ transient enhancement is a spine-specific function of the RyR. We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines. Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.

No MeSH data available.


Modelling of RyR mediated intraspine Ca2+ nanodomains.(a) Simulated linescan of the time course of [Ca2+] along a 200 nm line between the RyR located within the spine and VGCCs distributed across the opposite membrane surface. Black triangles correspond to bAPs in a 5 AP burst. Simulations were run with 200 μM fluo-4FF (top), 200 μM fluo-5F (middle) and 500 μM fluo-5F (bottom) as buffers. (b) Same as in (a) with RyRs omitted (VGCCs only). (c) [Ca2+] over time at a distance of 50 nm from the RyR channel pore (lines marked with x and o in a and b). Straight lines correspond to a scenario with RyRs and VGCCs, dotted lines to a scenario with VGCCs only. Different colours correspond to 200 μM fluo-4FF (black, top), 200 μM fluo-5F (blue, middle), and 500 μM fluo-5F (green, bottom) as buffers. (d) Spatial distribution of [Ca2+] maxima after 5th bAP with VGCC activation only (dotted line) or after RyR opening following 2nd bAP (solid lines) under different buffering conditions: 200 μM fluo-4FF (black), 200 μM fluo-5F (blue) and 500 μM fluo-5F (green). (e) Effect sizes. Plot of normalized bAP-Ca2+ transient enhancement 15 to 20 min after stimulation onset in all spines measured under different conditions. Black: 200 μM fluo-4FF, +19 ± 4%, n = 92/43 spines/cells; blue: 200 μM fluo-5F, +4 ± 5%, n = 31/7 spines/cells; grey: CPA (VGCCs only), -1 ± 5%, n = 31/11 spines/cells; green: 500 μM fluo-5F, -10 ± 3%, n = 68/24 spines/cells.
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pbio.1002181.g008: Modelling of RyR mediated intraspine Ca2+ nanodomains.(a) Simulated linescan of the time course of [Ca2+] along a 200 nm line between the RyR located within the spine and VGCCs distributed across the opposite membrane surface. Black triangles correspond to bAPs in a 5 AP burst. Simulations were run with 200 μM fluo-4FF (top), 200 μM fluo-5F (middle) and 500 μM fluo-5F (bottom) as buffers. (b) Same as in (a) with RyRs omitted (VGCCs only). (c) [Ca2+] over time at a distance of 50 nm from the RyR channel pore (lines marked with x and o in a and b). Straight lines correspond to a scenario with RyRs and VGCCs, dotted lines to a scenario with VGCCs only. Different colours correspond to 200 μM fluo-4FF (black, top), 200 μM fluo-5F (blue, middle), and 500 μM fluo-5F (green, bottom) as buffers. (d) Spatial distribution of [Ca2+] maxima after 5th bAP with VGCC activation only (dotted line) or after RyR opening following 2nd bAP (solid lines) under different buffering conditions: 200 μM fluo-4FF (black), 200 μM fluo-5F (blue) and 500 μM fluo-5F (green). (e) Effect sizes. Plot of normalized bAP-Ca2+ transient enhancement 15 to 20 min after stimulation onset in all spines measured under different conditions. Black: 200 μM fluo-4FF, +19 ± 4%, n = 92/43 spines/cells; blue: 200 μM fluo-5F, +4 ± 5%, n = 31/7 spines/cells; grey: CPA (VGCCs only), -1 ± 5%, n = 31/11 spines/cells; green: 500 μM fluo-5F, -10 ± 3%, n = 68/24 spines/cells.

Mentions: Ca2+ signalling domains within a spine cannot be temporally and spatially resolved with two-photon or confocal Ca2+ imaging. We therefore modelled spine Ca2+ dynamics. Our results were consistent with the idea that RyR Ca2+ domains trigger the activation of downstream effectors. We assumed a three-dimensional domain with membrane channels on one side and a single RyR on the opposite side (200 nm distance, Fig 8A and 8B). Reaction-diffusion equations for release and buffered diffusion of Ca2+ in the spine were numerically solved for given sequences of Ca2+ influx. APs led to opening of evenly distributed voltage-gated channels in the membrane, which in turn raised intracellular Ca2+ concentrations to about 1 μM. Although existing kinetic models of the RyR guarantee the dynamic opening of the receptor channel by Ca2+ concentrations in this range, we here implemented opening of this single RyR after doublet firing by default.


Ryanodine Receptor Activation Induces Long-Term Plasticity of Spine Calcium Dynamics.

Johenning FW, Theis AK, Pannasch U, Rückl M, Rüdiger S, Schmitz D - PLoS Biol. (2015)

Modelling of RyR mediated intraspine Ca2+ nanodomains.(a) Simulated linescan of the time course of [Ca2+] along a 200 nm line between the RyR located within the spine and VGCCs distributed across the opposite membrane surface. Black triangles correspond to bAPs in a 5 AP burst. Simulations were run with 200 μM fluo-4FF (top), 200 μM fluo-5F (middle) and 500 μM fluo-5F (bottom) as buffers. (b) Same as in (a) with RyRs omitted (VGCCs only). (c) [Ca2+] over time at a distance of 50 nm from the RyR channel pore (lines marked with x and o in a and b). Straight lines correspond to a scenario with RyRs and VGCCs, dotted lines to a scenario with VGCCs only. Different colours correspond to 200 μM fluo-4FF (black, top), 200 μM fluo-5F (blue, middle), and 500 μM fluo-5F (green, bottom) as buffers. (d) Spatial distribution of [Ca2+] maxima after 5th bAP with VGCC activation only (dotted line) or after RyR opening following 2nd bAP (solid lines) under different buffering conditions: 200 μM fluo-4FF (black), 200 μM fluo-5F (blue) and 500 μM fluo-5F (green). (e) Effect sizes. Plot of normalized bAP-Ca2+ transient enhancement 15 to 20 min after stimulation onset in all spines measured under different conditions. Black: 200 μM fluo-4FF, +19 ± 4%, n = 92/43 spines/cells; blue: 200 μM fluo-5F, +4 ± 5%, n = 31/7 spines/cells; grey: CPA (VGCCs only), -1 ± 5%, n = 31/11 spines/cells; green: 500 μM fluo-5F, -10 ± 3%, n = 68/24 spines/cells.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476683&req=5

pbio.1002181.g008: Modelling of RyR mediated intraspine Ca2+ nanodomains.(a) Simulated linescan of the time course of [Ca2+] along a 200 nm line between the RyR located within the spine and VGCCs distributed across the opposite membrane surface. Black triangles correspond to bAPs in a 5 AP burst. Simulations were run with 200 μM fluo-4FF (top), 200 μM fluo-5F (middle) and 500 μM fluo-5F (bottom) as buffers. (b) Same as in (a) with RyRs omitted (VGCCs only). (c) [Ca2+] over time at a distance of 50 nm from the RyR channel pore (lines marked with x and o in a and b). Straight lines correspond to a scenario with RyRs and VGCCs, dotted lines to a scenario with VGCCs only. Different colours correspond to 200 μM fluo-4FF (black, top), 200 μM fluo-5F (blue, middle), and 500 μM fluo-5F (green, bottom) as buffers. (d) Spatial distribution of [Ca2+] maxima after 5th bAP with VGCC activation only (dotted line) or after RyR opening following 2nd bAP (solid lines) under different buffering conditions: 200 μM fluo-4FF (black), 200 μM fluo-5F (blue) and 500 μM fluo-5F (green). (e) Effect sizes. Plot of normalized bAP-Ca2+ transient enhancement 15 to 20 min after stimulation onset in all spines measured under different conditions. Black: 200 μM fluo-4FF, +19 ± 4%, n = 92/43 spines/cells; blue: 200 μM fluo-5F, +4 ± 5%, n = 31/7 spines/cells; grey: CPA (VGCCs only), -1 ± 5%, n = 31/11 spines/cells; green: 500 μM fluo-5F, -10 ± 3%, n = 68/24 spines/cells.
Mentions: Ca2+ signalling domains within a spine cannot be temporally and spatially resolved with two-photon or confocal Ca2+ imaging. We therefore modelled spine Ca2+ dynamics. Our results were consistent with the idea that RyR Ca2+ domains trigger the activation of downstream effectors. We assumed a three-dimensional domain with membrane channels on one side and a single RyR on the opposite side (200 nm distance, Fig 8A and 8B). Reaction-diffusion equations for release and buffered diffusion of Ca2+ in the spine were numerically solved for given sequences of Ca2+ influx. APs led to opening of evenly distributed voltage-gated channels in the membrane, which in turn raised intracellular Ca2+ concentrations to about 1 μM. Although existing kinetic models of the RyR guarantee the dynamic opening of the receptor channel by Ca2+ concentrations in this range, we here implemented opening of this single RyR after doublet firing by default.

Bottom Line: Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger.We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines.Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Center, Charité-Universitätsmedizin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.

ABSTRACT
A key feature of signalling in dendritic spines is the synapse-specific transduction of short electrical signals into biochemical responses. Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger. Upon action potential firing, the majority of spines are subject to global back-propagating action potential (bAP) Ca2+ transients. These transients translate neuronal suprathreshold activation into intracellular biochemical events. Using a combination of electrophysiology, two-photon Ca2+ imaging, and modelling, we demonstrate that bAPs are electrochemically coupled to Ca2+ release from intracellular stores via ryanodine receptors (RyRs). We describe a new function mediated by spine RyRs: the activity-dependent long-term enhancement of the bAP-Ca2+ transient. Spines regulate bAP Ca2+ influx independent of each other, as bAP-Ca2+ transient enhancement is compartmentalized and independent of the dendritic Ca2+ transient. Furthermore, this functional state change depends exclusively on bAPs travelling antidromically into dendrites and spines. Induction, but not expression, of bAP-Ca2+ transient enhancement is a spine-specific function of the RyR. We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines. Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.

No MeSH data available.