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Upward synaptic scaling is dependent on neurotransmission rather than spiking.

Fong MF, Newman JP, Potter SM, Wenner P - Nat Commun (2015)

Bottom Line: The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate.This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling.Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Laboratory for Neuroengineering, Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA [3] Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Homeostatic plasticity encompasses a set of mechanisms that are thought to stabilize firing rates in neural circuits. The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate. While reduced spiking is thought to trigger upscaling, an alternative possibility is that reduced glutamatergic transmission generates this plasticity directly. However, spiking and neurotransmission are tightly coupled, so it has been difficult to determine their independent roles in the scaling process. Here we combined chronic multielectrode recording, closed-loop optogenetic stimulation, and pharmacology to show that reduced glutamatergic transmission directly triggers cell-wide synaptic upscaling. This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling. Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.

No MeSH data available.


Related in: MedlinePlus

Optogenetic stimulation recreates spontaneous-like bursting during AMPAergic transmission blockade.(a) Confocal micrograph of neurons in a cortical culture expressing ChR2-eYFP. Microelectrodes are circled in white. Scale bars, 200 μm (left), 50 μm (right). (b) Left, voltage traces recorded from a single microelectrode during a spontaneous burst (top) and a photostimulation-evoked burst following the addition of CNQX (40 μM, bottom). The blue arrow denotes the timing of the light pulse stimulation and the blue rectangle indicates the pulse duration (10 ms). The rastergrams (coloured vertical bars) below each voltage trace denote the spike times of three different extracellular units captured on the electrode. Right, expanded voltage traces showing all spikes detected during burst (separate units displayed in different colours). Scale bars, 50 μV, 200 ms (left); 25 μV, 1 ms (right). (c) Rastergrams showing spike times recorded across all electrodes during a spontaneous burst (top) and an optically evoked burst after the addition of CNQX (middle). The recruitment of spikes across the MEA is similar between the two conditions. Blue arrow denotes the timing of the light pulse. An expanded rastergram shows spikes occurring at burst onset (bottom) and blue shading denotes when light is on. Scale bars, 100 ms (top and middle), 5 ms (bottom). (d) MEA-wide firing rate computed during bursts shown in c, denoted by black lines. All bursts occurring during the 3-h pre-drug condition (top) and 24-h CNQX with photostimulation condition (middle) are plotted in grey. Zooming out in time (bottom) shows that each stimulus (blue arrows) reliably evokes a burst. Bin size, 10 ms. Scale bars, 100 ms (top and middle), 2 min (bottom). (e) Calcium transients (▵F/F) for two different ROIs and a 10-ROI average are shown during a spontaneous burst, an optically-evoked burst, and an optically evoked burst in the presence of CNQX. All traces were taken from the same culture. Fast calcium transient immediately follows the 10-ms pulse of blue light stimulation (direct illumination through filters, not dependent on calcium indicator). Scale bars, 2 s, 40% ΔF/F. (f) Rastergrams showing spike times for all MEA electrodes recorded concurrently with calcium transients shown in e. Scale bar, 2 s.
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f4: Optogenetic stimulation recreates spontaneous-like bursting during AMPAergic transmission blockade.(a) Confocal micrograph of neurons in a cortical culture expressing ChR2-eYFP. Microelectrodes are circled in white. Scale bars, 200 μm (left), 50 μm (right). (b) Left, voltage traces recorded from a single microelectrode during a spontaneous burst (top) and a photostimulation-evoked burst following the addition of CNQX (40 μM, bottom). The blue arrow denotes the timing of the light pulse stimulation and the blue rectangle indicates the pulse duration (10 ms). The rastergrams (coloured vertical bars) below each voltage trace denote the spike times of three different extracellular units captured on the electrode. Right, expanded voltage traces showing all spikes detected during burst (separate units displayed in different colours). Scale bars, 50 μV, 200 ms (left); 25 μV, 1 ms (right). (c) Rastergrams showing spike times recorded across all electrodes during a spontaneous burst (top) and an optically evoked burst after the addition of CNQX (middle). The recruitment of spikes across the MEA is similar between the two conditions. Blue arrow denotes the timing of the light pulse. An expanded rastergram shows spikes occurring at burst onset (bottom) and blue shading denotes when light is on. Scale bars, 100 ms (top and middle), 5 ms (bottom). (d) MEA-wide firing rate computed during bursts shown in c, denoted by black lines. All bursts occurring during the 3-h pre-drug condition (top) and 24-h CNQX with photostimulation condition (middle) are plotted in grey. Zooming out in time (bottom) shows that each stimulus (blue arrows) reliably evokes a burst. Bin size, 10 ms. Scale bars, 100 ms (top and middle), 2 min (bottom). (e) Calcium transients (▵F/F) for two different ROIs and a 10-ROI average are shown during a spontaneous burst, an optically-evoked burst, and an optically evoked burst in the presence of CNQX. All traces were taken from the same culture. Fast calcium transient immediately follows the 10-ms pulse of blue light stimulation (direct illumination through filters, not dependent on calcium indicator). Scale bars, 2 s, 40% ΔF/F. (f) Rastergrams showing spike times for all MEA electrodes recorded concurrently with calcium transients shown in e. Scale bar, 2 s.

Mentions: In order to examine the effects of reducing AMPAergic transmission independent of spiking, we developed a closed-loop optical stimulation system for restoring normal levels of spiking activity during chronic CNQX treatment. We used an adenoassociated virus to infect cells with the channelrhodopsin-2 gene (ChR2; H134R mutant30) in cultured neurons, and observed expression throughout the culture within a week (Fig. 4a). To deliver optical stimuli, we used a custom light-emitting diode (LED) stimulator (see Methods). Blue light (465 nm) was passed through a randomized fibre bundle and fed to a custom optical train, providing uniformly distributed illumination in the plane of the culture (Fig. 5, left; 10.1 mW mm−2).


Upward synaptic scaling is dependent on neurotransmission rather than spiking.

Fong MF, Newman JP, Potter SM, Wenner P - Nat Commun (2015)

Optogenetic stimulation recreates spontaneous-like bursting during AMPAergic transmission blockade.(a) Confocal micrograph of neurons in a cortical culture expressing ChR2-eYFP. Microelectrodes are circled in white. Scale bars, 200 μm (left), 50 μm (right). (b) Left, voltage traces recorded from a single microelectrode during a spontaneous burst (top) and a photostimulation-evoked burst following the addition of CNQX (40 μM, bottom). The blue arrow denotes the timing of the light pulse stimulation and the blue rectangle indicates the pulse duration (10 ms). The rastergrams (coloured vertical bars) below each voltage trace denote the spike times of three different extracellular units captured on the electrode. Right, expanded voltage traces showing all spikes detected during burst (separate units displayed in different colours). Scale bars, 50 μV, 200 ms (left); 25 μV, 1 ms (right). (c) Rastergrams showing spike times recorded across all electrodes during a spontaneous burst (top) and an optically evoked burst after the addition of CNQX (middle). The recruitment of spikes across the MEA is similar between the two conditions. Blue arrow denotes the timing of the light pulse. An expanded rastergram shows spikes occurring at burst onset (bottom) and blue shading denotes when light is on. Scale bars, 100 ms (top and middle), 5 ms (bottom). (d) MEA-wide firing rate computed during bursts shown in c, denoted by black lines. All bursts occurring during the 3-h pre-drug condition (top) and 24-h CNQX with photostimulation condition (middle) are plotted in grey. Zooming out in time (bottom) shows that each stimulus (blue arrows) reliably evokes a burst. Bin size, 10 ms. Scale bars, 100 ms (top and middle), 2 min (bottom). (e) Calcium transients (▵F/F) for two different ROIs and a 10-ROI average are shown during a spontaneous burst, an optically-evoked burst, and an optically evoked burst in the presence of CNQX. All traces were taken from the same culture. Fast calcium transient immediately follows the 10-ms pulse of blue light stimulation (direct illumination through filters, not dependent on calcium indicator). Scale bars, 2 s, 40% ΔF/F. (f) Rastergrams showing spike times for all MEA electrodes recorded concurrently with calcium transients shown in e. Scale bar, 2 s.
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Related In: Results  -  Collection

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f4: Optogenetic stimulation recreates spontaneous-like bursting during AMPAergic transmission blockade.(a) Confocal micrograph of neurons in a cortical culture expressing ChR2-eYFP. Microelectrodes are circled in white. Scale bars, 200 μm (left), 50 μm (right). (b) Left, voltage traces recorded from a single microelectrode during a spontaneous burst (top) and a photostimulation-evoked burst following the addition of CNQX (40 μM, bottom). The blue arrow denotes the timing of the light pulse stimulation and the blue rectangle indicates the pulse duration (10 ms). The rastergrams (coloured vertical bars) below each voltage trace denote the spike times of three different extracellular units captured on the electrode. Right, expanded voltage traces showing all spikes detected during burst (separate units displayed in different colours). Scale bars, 50 μV, 200 ms (left); 25 μV, 1 ms (right). (c) Rastergrams showing spike times recorded across all electrodes during a spontaneous burst (top) and an optically evoked burst after the addition of CNQX (middle). The recruitment of spikes across the MEA is similar between the two conditions. Blue arrow denotes the timing of the light pulse. An expanded rastergram shows spikes occurring at burst onset (bottom) and blue shading denotes when light is on. Scale bars, 100 ms (top and middle), 5 ms (bottom). (d) MEA-wide firing rate computed during bursts shown in c, denoted by black lines. All bursts occurring during the 3-h pre-drug condition (top) and 24-h CNQX with photostimulation condition (middle) are plotted in grey. Zooming out in time (bottom) shows that each stimulus (blue arrows) reliably evokes a burst. Bin size, 10 ms. Scale bars, 100 ms (top and middle), 2 min (bottom). (e) Calcium transients (▵F/F) for two different ROIs and a 10-ROI average are shown during a spontaneous burst, an optically-evoked burst, and an optically evoked burst in the presence of CNQX. All traces were taken from the same culture. Fast calcium transient immediately follows the 10-ms pulse of blue light stimulation (direct illumination through filters, not dependent on calcium indicator). Scale bars, 2 s, 40% ΔF/F. (f) Rastergrams showing spike times for all MEA electrodes recorded concurrently with calcium transients shown in e. Scale bar, 2 s.
Mentions: In order to examine the effects of reducing AMPAergic transmission independent of spiking, we developed a closed-loop optical stimulation system for restoring normal levels of spiking activity during chronic CNQX treatment. We used an adenoassociated virus to infect cells with the channelrhodopsin-2 gene (ChR2; H134R mutant30) in cultured neurons, and observed expression throughout the culture within a week (Fig. 4a). To deliver optical stimuli, we used a custom light-emitting diode (LED) stimulator (see Methods). Blue light (465 nm) was passed through a randomized fibre bundle and fed to a custom optical train, providing uniformly distributed illumination in the plane of the culture (Fig. 5, left; 10.1 mW mm−2).

Bottom Line: The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate.This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling.Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Laboratory for Neuroengineering, Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA [3] Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Homeostatic plasticity encompasses a set of mechanisms that are thought to stabilize firing rates in neural circuits. The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate. While reduced spiking is thought to trigger upscaling, an alternative possibility is that reduced glutamatergic transmission generates this plasticity directly. However, spiking and neurotransmission are tightly coupled, so it has been difficult to determine their independent roles in the scaling process. Here we combined chronic multielectrode recording, closed-loop optogenetic stimulation, and pharmacology to show that reduced glutamatergic transmission directly triggers cell-wide synaptic upscaling. This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling. Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.

No MeSH data available.


Related in: MedlinePlus