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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.


Related in: MedlinePlus

A subpopulation of spines undergoes activity-dependent enhancement.(a1) Averaged baseline bAP-Ca2+ transients 0 to 5 min after bAP stimulation onset (grey traces) and averaged bAP-Ca2+ transients 15 to 20 min after bAP stimulation onset of 2 adjacent spines (black and blue) and the dendrite (red). (a2) Z-projection of the imaged dendritic segment (scale bar corresponds to 2 μm). Asterisks mark imaged spines and dendritic segment. (a3) Time plots of normalized single sweep amplitudes. (b) The averaged baseline amplitude is plotted against bAP-Ca2+ transient enhancement 15 to 20 min after bAP stimulation onset (r = -0.45, n = 92/43 spines/cells, p < 0.0001, Spearman’s rank order test). Spines with pre induction amplitudes <0.041 ∆G/R are depicted in black (n = 53/31 spines/cells), spines with pre-induction amplitudes >0.041 in blue (n = 39/22 spines/cells). (c) Time plot of normalized bAP-Ca2+ transients demonstrates selective enhancement of spines with baseline amplitudes <0.041 ∆G/R (black) when compared to dendrites (red) and spines with baseline amplitudes >0.041 ∆G/R (blue). Interval 15 to 20 min after bAP stimulation onset used for quantification of normalized enhancement is shaded in grey. (d1) Bar graph of normalized enhancement 15 to 20 min after bAP stimulation onset. Enhancement for spines with baseline ∆G/R<0.041 (black, +33 ± 6%, n = 53/31 spines/cells) is significantly larger than in spines with baseline ∆G/R>0.041 (blue, -1 ± 3%, n = 39/22 spines/cells, p < 0.001) and dendrites adjacent to spines with baseline ∆G/R<0.041 (red, -5 ± 5%, n = 23/23, dendrites/cells, p < 0.001, Kruskal Wallis Test with Dunn’s posthoc comparison). (d2) Cumulative distribution plot of normalized enhancement 15 to 20 min after bAP stimulation onset (shaded grey in c). Data are expressed as mean SEM *** p < 0.001.
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pbio.1002181.g003: A subpopulation of spines undergoes activity-dependent enhancement.(a1) Averaged baseline bAP-Ca2+ transients 0 to 5 min after bAP stimulation onset (grey traces) and averaged bAP-Ca2+ transients 15 to 20 min after bAP stimulation onset of 2 adjacent spines (black and blue) and the dendrite (red). (a2) Z-projection of the imaged dendritic segment (scale bar corresponds to 2 μm). Asterisks mark imaged spines and dendritic segment. (a3) Time plots of normalized single sweep amplitudes. (b) The averaged baseline amplitude is plotted against bAP-Ca2+ transient enhancement 15 to 20 min after bAP stimulation onset (r = -0.45, n = 92/43 spines/cells, p < 0.0001, Spearman’s rank order test). Spines with pre induction amplitudes <0.041 ∆G/R are depicted in black (n = 53/31 spines/cells), spines with pre-induction amplitudes >0.041 in blue (n = 39/22 spines/cells). (c) Time plot of normalized bAP-Ca2+ transients demonstrates selective enhancement of spines with baseline amplitudes <0.041 ∆G/R (black) when compared to dendrites (red) and spines with baseline amplitudes >0.041 ∆G/R (blue). Interval 15 to 20 min after bAP stimulation onset used for quantification of normalized enhancement is shaded in grey. (d1) Bar graph of normalized enhancement 15 to 20 min after bAP stimulation onset. Enhancement for spines with baseline ∆G/R<0.041 (black, +33 ± 6%, n = 53/31 spines/cells) is significantly larger than in spines with baseline ∆G/R>0.041 (blue, -1 ± 3%, n = 39/22 spines/cells, p < 0.001) and dendrites adjacent to spines with baseline ∆G/R<0.041 (red, -5 ± 5%, n = 23/23, dendrites/cells, p < 0.001, Kruskal Wallis Test with Dunn’s posthoc comparison). (d2) Cumulative distribution plot of normalized enhancement 15 to 20 min after bAP stimulation onset (shaded grey in c). Data are expressed as mean SEM *** p < 0.001.

Mentions: To quantify spine-specific enhancement, bAP-Ca2+ transient amplitudes following a 15 min stimulation paradigm (Fig 2A2) were normalized to the baseline amplitudes (Fig 3C; see Methods and S6 Fig on amplitude measurements). In layer 2 cells of the MEC, a population of 92 spines from 43 cells fulfilled our quality criteria for long-term measurements (see Methods). As opposed to our fluo-5F control doublet timelines from Fig 1C, enhancement under these conditions was significantly different from a theoretical median of 0% change in the time interval 15 to 20 min after the onset of stimulation (p < 0.0001, Wilcoxon-signed rank test). This new protocol enabled us to study enhancement in a more systematic fashion with a larger effect size in a shorter experimental time window. 42% of the spines could be classified as plastic, which means they displayed bAP-Ca2+ transient enhancement by >20%. Spines with changes of the bAP-Ca2+ transient of <20% were defined as static spines.


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)

A subpopulation of spines undergoes activity-dependent enhancement.(a1) Averaged baseline bAP-Ca2+ transients 0 to 5 min after bAP stimulation onset (grey traces) and averaged bAP-Ca2+ transients 15 to 20 min after bAP stimulation onset of 2 adjacent spines (black and blue) and the dendrite (red). (a2) Z-projection of the imaged dendritic segment (scale bar corresponds to 2 μm). Asterisks mark imaged spines and dendritic segment. (a3) Time plots of normalized single sweep amplitudes. (b) The averaged baseline amplitude is plotted against bAP-Ca2+ transient enhancement 15 to 20 min after bAP stimulation onset (r = -0.45, n = 92/43 spines/cells, p < 0.0001, Spearman’s rank order test). Spines with pre induction amplitudes <0.041 ∆G/R are depicted in black (n = 53/31 spines/cells), spines with pre-induction amplitudes >0.041 in blue (n = 39/22 spines/cells). (c) Time plot of normalized bAP-Ca2+ transients demonstrates selective enhancement of spines with baseline amplitudes <0.041 ∆G/R (black) when compared to dendrites (red) and spines with baseline amplitudes >0.041 ∆G/R (blue). Interval 15 to 20 min after bAP stimulation onset used for quantification of normalized enhancement is shaded in grey. (d1) Bar graph of normalized enhancement 15 to 20 min after bAP stimulation onset. Enhancement for spines with baseline ∆G/R<0.041 (black, +33 ± 6%, n = 53/31 spines/cells) is significantly larger than in spines with baseline ∆G/R>0.041 (blue, -1 ± 3%, n = 39/22 spines/cells, p < 0.001) and dendrites adjacent to spines with baseline ∆G/R<0.041 (red, -5 ± 5%, n = 23/23, dendrites/cells, p < 0.001, Kruskal Wallis Test with Dunn’s posthoc comparison). (d2) Cumulative distribution plot of normalized enhancement 15 to 20 min after bAP stimulation onset (shaded grey in c). Data are expressed as mean SEM *** p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pbio.1002181.g003: A subpopulation of spines undergoes activity-dependent enhancement.(a1) Averaged baseline bAP-Ca2+ transients 0 to 5 min after bAP stimulation onset (grey traces) and averaged bAP-Ca2+ transients 15 to 20 min after bAP stimulation onset of 2 adjacent spines (black and blue) and the dendrite (red). (a2) Z-projection of the imaged dendritic segment (scale bar corresponds to 2 μm). Asterisks mark imaged spines and dendritic segment. (a3) Time plots of normalized single sweep amplitudes. (b) The averaged baseline amplitude is plotted against bAP-Ca2+ transient enhancement 15 to 20 min after bAP stimulation onset (r = -0.45, n = 92/43 spines/cells, p < 0.0001, Spearman’s rank order test). Spines with pre induction amplitudes <0.041 ∆G/R are depicted in black (n = 53/31 spines/cells), spines with pre-induction amplitudes >0.041 in blue (n = 39/22 spines/cells). (c) Time plot of normalized bAP-Ca2+ transients demonstrates selective enhancement of spines with baseline amplitudes <0.041 ∆G/R (black) when compared to dendrites (red) and spines with baseline amplitudes >0.041 ∆G/R (blue). Interval 15 to 20 min after bAP stimulation onset used for quantification of normalized enhancement is shaded in grey. (d1) Bar graph of normalized enhancement 15 to 20 min after bAP stimulation onset. Enhancement for spines with baseline ∆G/R<0.041 (black, +33 ± 6%, n = 53/31 spines/cells) is significantly larger than in spines with baseline ∆G/R>0.041 (blue, -1 ± 3%, n = 39/22 spines/cells, p < 0.001) and dendrites adjacent to spines with baseline ∆G/R<0.041 (red, -5 ± 5%, n = 23/23, dendrites/cells, p < 0.001, Kruskal Wallis Test with Dunn’s posthoc comparison). (d2) Cumulative distribution plot of normalized enhancement 15 to 20 min after bAP stimulation onset (shaded grey in c). Data are expressed as mean SEM *** p < 0.001.
Mentions: To quantify spine-specific enhancement, bAP-Ca2+ transient amplitudes following a 15 min stimulation paradigm (Fig 2A2) were normalized to the baseline amplitudes (Fig 3C; see Methods and S6 Fig on amplitude measurements). In layer 2 cells of the MEC, a population of 92 spines from 43 cells fulfilled our quality criteria for long-term measurements (see Methods). As opposed to our fluo-5F control doublet timelines from Fig 1C, enhancement under these conditions was significantly different from a theoretical median of 0% change in the time interval 15 to 20 min after the onset of stimulation (p < 0.0001, Wilcoxon-signed rank test). This new protocol enabled us to study enhancement in a more systematic fashion with a larger effect size in a shorter experimental time window. 42% of the spines could be classified as plastic, which means they displayed bAP-Ca2+ transient enhancement by >20%. Spines with changes of the bAP-Ca2+ transient of <20% were defined as static spines.

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.


Related in: MedlinePlus