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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

Closed-loop optical stimulation restores spiking activity and calcium transients following AMPAergic transmission blockade.(a) Top, MEA-wide firing rate from example recording before and during application of CNQX (40 μM), with the pre-CNQX firing rate restored using closed-loop photostimulation. The closed-loop controller begins 5 min after CNQX is added to verify that the drug has taken effect. Bin size, 1 s. Bottom, rastergrams show 15-min segments of spiking activity at different time points throughout the recording. Neurons throughout the culture contribute to restored spiking activity during the entire 24-h CNQX treatment. Scale bar, 2 min. (b) The mean MEA-wide firing rate over time for CNQX-treated cultures with restored spiking (n=5 cultures). Control and CNQX values from Fig. 2b are shown for comparison (controls, n=12 cultures; CNQX, n=13 cultures). Closed-loop stimulation effectively locked firing rate to pre-CNQX levels. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate, burst rate and interburst firing rate for CNQX+photostimulation cultures over the 24-h treatment window, with control and CNQX values from Fig. 2c shown for comparison. CNQX-treated cultures with restored spiking showed no differences in firing rate or burst rate compared with vehicle-treated controls (MEA-wide firing rate, 100.2±0.4%, P<0.6; burst rate, 97.7±32.0%, P<0.9; interburst firing rate, 96.2±24.9%, P<0.9). Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4.
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f6: Closed-loop optical stimulation restores spiking activity and calcium transients following AMPAergic transmission blockade.(a) Top, MEA-wide firing rate from example recording before and during application of CNQX (40 μM), with the pre-CNQX firing rate restored using closed-loop photostimulation. The closed-loop controller begins 5 min after CNQX is added to verify that the drug has taken effect. Bin size, 1 s. Bottom, rastergrams show 15-min segments of spiking activity at different time points throughout the recording. Neurons throughout the culture contribute to restored spiking activity during the entire 24-h CNQX treatment. Scale bar, 2 min. (b) The mean MEA-wide firing rate over time for CNQX-treated cultures with restored spiking (n=5 cultures). Control and CNQX values from Fig. 2b are shown for comparison (controls, n=12 cultures; CNQX, n=13 cultures). Closed-loop stimulation effectively locked firing rate to pre-CNQX levels. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate, burst rate and interburst firing rate for CNQX+photostimulation cultures over the 24-h treatment window, with control and CNQX values from Fig. 2c shown for comparison. CNQX-treated cultures with restored spiking showed no differences in firing rate or burst rate compared with vehicle-treated controls (MEA-wide firing rate, 100.2±0.4%, P<0.6; burst rate, 97.7±32.0%, P<0.9; interburst firing rate, 96.2±24.9%, P<0.9). Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4.

Mentions: To achieve precise control of the MEA-wide firing rate, we delivered optical stimulation in real-time based on spiking activity recorded through the MEA31. The MEA-wide firing rate was calculated every 10 ms, and a brief pulse (10 ms) of blue light was delivered if the integrated error between the target and measured firing rate became positive (Fig. 5, methods). In order to restore normal levels of spiking during an AMPAR blockade, we treated cultures with CNQX and began closed-loop optical stimulation with a target spiking level set to the pre-drug firing rate (Fig. 6a). Closed-loop optical stimulation effectively restored the pre-drug firing rate throughout CNQX application (Fig. 6b) while preserving spiking correlations between electrodes (Supplementary Fig. 5). Further, our controller effectively restored burst rate (Fig. 6c) and burst shape (Supplementary Fig. 4).


Upward synaptic scaling is dependent on neurotransmission rather than spiking.

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

Closed-loop optical stimulation restores spiking activity and calcium transients following AMPAergic transmission blockade.(a) Top, MEA-wide firing rate from example recording before and during application of CNQX (40 μM), with the pre-CNQX firing rate restored using closed-loop photostimulation. The closed-loop controller begins 5 min after CNQX is added to verify that the drug has taken effect. Bin size, 1 s. Bottom, rastergrams show 15-min segments of spiking activity at different time points throughout the recording. Neurons throughout the culture contribute to restored spiking activity during the entire 24-h CNQX treatment. Scale bar, 2 min. (b) The mean MEA-wide firing rate over time for CNQX-treated cultures with restored spiking (n=5 cultures). Control and CNQX values from Fig. 2b are shown for comparison (controls, n=12 cultures; CNQX, n=13 cultures). Closed-loop stimulation effectively locked firing rate to pre-CNQX levels. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate, burst rate and interburst firing rate for CNQX+photostimulation cultures over the 24-h treatment window, with control and CNQX values from Fig. 2c shown for comparison. CNQX-treated cultures with restored spiking showed no differences in firing rate or burst rate compared with vehicle-treated controls (MEA-wide firing rate, 100.2±0.4%, P<0.6; burst rate, 97.7±32.0%, P<0.9; interburst firing rate, 96.2±24.9%, P<0.9). Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4355957&req=5

f6: Closed-loop optical stimulation restores spiking activity and calcium transients following AMPAergic transmission blockade.(a) Top, MEA-wide firing rate from example recording before and during application of CNQX (40 μM), with the pre-CNQX firing rate restored using closed-loop photostimulation. The closed-loop controller begins 5 min after CNQX is added to verify that the drug has taken effect. Bin size, 1 s. Bottom, rastergrams show 15-min segments of spiking activity at different time points throughout the recording. Neurons throughout the culture contribute to restored spiking activity during the entire 24-h CNQX treatment. Scale bar, 2 min. (b) The mean MEA-wide firing rate over time for CNQX-treated cultures with restored spiking (n=5 cultures). Control and CNQX values from Fig. 2b are shown for comparison (controls, n=12 cultures; CNQX, n=13 cultures). Closed-loop stimulation effectively locked firing rate to pre-CNQX levels. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate, burst rate and interburst firing rate for CNQX+photostimulation cultures over the 24-h treatment window, with control and CNQX values from Fig. 2c shown for comparison. CNQX-treated cultures with restored spiking showed no differences in firing rate or burst rate compared with vehicle-treated controls (MEA-wide firing rate, 100.2±0.4%, P<0.6; burst rate, 97.7±32.0%, P<0.9; interburst firing rate, 96.2±24.9%, P<0.9). Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4.
Mentions: To achieve precise control of the MEA-wide firing rate, we delivered optical stimulation in real-time based on spiking activity recorded through the MEA31. The MEA-wide firing rate was calculated every 10 ms, and a brief pulse (10 ms) of blue light was delivered if the integrated error between the target and measured firing rate became positive (Fig. 5, methods). In order to restore normal levels of spiking during an AMPAR blockade, we treated cultures with CNQX and began closed-loop optical stimulation with a target spiking level set to the pre-drug firing rate (Fig. 6a). Closed-loop optical stimulation effectively restored the pre-drug firing rate throughout CNQX application (Fig. 6b) while preserving spiking correlations between electrodes (Supplementary Fig. 5). Further, our controller effectively restored burst rate (Fig. 6c) and burst shape (Supplementary Fig. 4).

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