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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

Spiking and bursting persist during AMPAergic transmission blockade.(a) MEA-wide firing rate histograms from example recordings before and during application of TTX (1 μM) or CNQX (40 μM). Bin size, 1 s. (b) The mean MEA-wide firing rate over time for different conditions (vehicle-treated controls, n=12 cultures; TTX, n=8 cultures; CNQX, n=13 cultures). Values are normalized to the firing rate during the 3-h window before drug/vehicle application. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate (control, 97.3±4.6%; TTX, 1.1±0.5%; CNQX, 46.2±4.1%; P<10−6), burst rate (control, 105.8±10.0%; TTX, 0%; CNQX, 31.2±4.8%; P<10−6) and interburst firing rate (control, 108.1±12.7%; TTX, 3.6±1.5%; CNQX, 77.4±16.8%; P<10−4) over the entire 24-h treatment window, normalized to pre-drug values. Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4. Error bars, s.e.m.
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f2: Spiking and bursting persist during AMPAergic transmission blockade.(a) MEA-wide firing rate histograms from example recordings before and during application of TTX (1 μM) or CNQX (40 μM). Bin size, 1 s. (b) The mean MEA-wide firing rate over time for different conditions (vehicle-treated controls, n=12 cultures; TTX, n=8 cultures; CNQX, n=13 cultures). Values are normalized to the firing rate during the 3-h window before drug/vehicle application. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate (control, 97.3±4.6%; TTX, 1.1±0.5%; CNQX, 46.2±4.1%; P<10−6), burst rate (control, 105.8±10.0%; TTX, 0%; CNQX, 31.2±4.8%; P<10−6) and interburst firing rate (control, 108.1±12.7%; TTX, 3.6±1.5%; CNQX, 77.4±16.8%; P<10−4) over the entire 24-h treatment window, normalized to pre-drug values. Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4. Error bars, s.e.m.

Mentions: We next examined how a 24-h blockade of either voltage-gated sodium channels or AMPA/kainate receptors modulated spiking and bursting activity. Both perturbations are thought to trigger upscaling by reducing spiking activity. Consistent with our expectations, the voltage-gated sodium channel blocker tetrodotoxin (TTX) eliminated spiking activity for the entire 24-h treatment (Fig. 2a,b). In contrast, the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) only partially reduced spiking activity compared with pre-drug levels152728 (Fig. 2a,b). The CNQX-induced reduction in the firing rate was primarily due to a reduction in burst frequency, while spiking during the interburst interval was not significantly affected (Fig. 2c). Spiking and bursting were reduced during the first few hours of the CNQX treatment, but typically began to recover by the end of 24 h (Fig. 2a,b). This recovery was highly variable across cultures (Fig. 2b, Supplementary Fig. 1a–d), and was likely facilitated by NMDAergic (N-methyl-D-aspartate) transmission2729 (Supplementary Fig. 2). Notably, any recovery could not have been caused by AMPAergic upscaling since AMPARs were blocked by CNQX. While the CNQX-induced reduction in spiking was variable, some degree of spiking and bursting always persisted, unlike cultures treated with TTX. The distinct effects of TTX and CNQX on spiking activity suggest that they could also have different effects on activity-dependent processes such as synaptic scaling.


Upward synaptic scaling is dependent on neurotransmission rather than spiking.

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

Spiking and bursting persist during AMPAergic transmission blockade.(a) MEA-wide firing rate histograms from example recordings before and during application of TTX (1 μM) or CNQX (40 μM). Bin size, 1 s. (b) The mean MEA-wide firing rate over time for different conditions (vehicle-treated controls, n=12 cultures; TTX, n=8 cultures; CNQX, n=13 cultures). Values are normalized to the firing rate during the 3-h window before drug/vehicle application. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate (control, 97.3±4.6%; TTX, 1.1±0.5%; CNQX, 46.2±4.1%; P<10−6), burst rate (control, 105.8±10.0%; TTX, 0%; CNQX, 31.2±4.8%; P<10−6) and interburst firing rate (control, 108.1±12.7%; TTX, 3.6±1.5%; CNQX, 77.4±16.8%; P<10−4) over the entire 24-h treatment window, normalized to pre-drug values. Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4. Error bars, s.e.m.
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f2: Spiking and bursting persist during AMPAergic transmission blockade.(a) MEA-wide firing rate histograms from example recordings before and during application of TTX (1 μM) or CNQX (40 μM). Bin size, 1 s. (b) The mean MEA-wide firing rate over time for different conditions (vehicle-treated controls, n=12 cultures; TTX, n=8 cultures; CNQX, n=13 cultures). Values are normalized to the firing rate during the 3-h window before drug/vehicle application. Bin size, 3 h. Error bars, s.d. (c) The mean MEA-wide firing rate (control, 97.3±4.6%; TTX, 1.1±0.5%; CNQX, 46.2±4.1%; P<10−6), burst rate (control, 105.8±10.0%; TTX, 0%; CNQX, 31.2±4.8%; P<10−6) and interburst firing rate (control, 108.1±12.7%; TTX, 3.6±1.5%; CNQX, 77.4±16.8%; P<10−4) over the entire 24-h treatment window, normalized to pre-drug values. Nonsignificant differences denoted by n.s. Significant differences denoted by *P<10−3, **P<10−4. Error bars, s.e.m.
Mentions: We next examined how a 24-h blockade of either voltage-gated sodium channels or AMPA/kainate receptors modulated spiking and bursting activity. Both perturbations are thought to trigger upscaling by reducing spiking activity. Consistent with our expectations, the voltage-gated sodium channel blocker tetrodotoxin (TTX) eliminated spiking activity for the entire 24-h treatment (Fig. 2a,b). In contrast, the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) only partially reduced spiking activity compared with pre-drug levels152728 (Fig. 2a,b). The CNQX-induced reduction in the firing rate was primarily due to a reduction in burst frequency, while spiking during the interburst interval was not significantly affected (Fig. 2c). Spiking and bursting were reduced during the first few hours of the CNQX treatment, but typically began to recover by the end of 24 h (Fig. 2a,b). This recovery was highly variable across cultures (Fig. 2b, Supplementary Fig. 1a–d), and was likely facilitated by NMDAergic (N-methyl-D-aspartate) transmission2729 (Supplementary Fig. 2). Notably, any recovery could not have been caused by AMPAergic upscaling since AMPARs were blocked by CNQX. While the CNQX-induced reduction in spiking was variable, some degree of spiking and bursting always persisted, unlike cultures treated with TTX. The distinct effects of TTX and CNQX on spiking activity suggest that they could also have different effects on activity-dependent processes such as synaptic scaling.

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