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Equalizing excitation-inhibition ratios across visual cortical neurons.

Xue M, Atallah BV, Scanziani M - Nature (2014)

Bottom Line: This matched inhibition is mediated by parvalbumin-expressing but not somatostatin-expressing inhibitory cells and results from the independent adjustment of synapses originating from individual parvalbumin-expressing cells targeting different pyramidal cells.Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity.Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between the cortex's two opposing forces is stabilized not only in time but also in space.

View Article: PubMed Central - PubMed

Affiliation: 1] Neurobiology Section, Division of Biological Sciences, Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, California 92093-0634, USA [2] Department of Neuroscience, University of California, San Diego, La Jolla, California 92093-0634, USA [3] Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.

ABSTRACT
The relationship between synaptic excitation and inhibition (E/I ratio), two opposing forces in the mammalian cerebral cortex, affects many cortical functions such as feature selectivity and gain. Individual pyramidal cells show stable E/I ratios in time despite fluctuating cortical activity levels. This is because when excitation increases, inhibition increases proportionally through the increased recruitment of inhibitory neurons, a phenomenon referred to as excitation-inhibition balance. However, little is known about the distribution of E/I ratios across pyramidal cells. Through their highly divergent axons, inhibitory neurons indiscriminately contact most neighbouring pyramidal cells. Is inhibition homogeneously distributed or is it individually matched to the different amounts of excitation received by distinct pyramidal cells? Here we discover that pyramidal cells in layer 2/3 of mouse primary visual cortex each receive inhibition in a similar proportion to their excitation. As a consequence, E/I ratios are equalized across pyramidal cells. This matched inhibition is mediated by parvalbumin-expressing but not somatostatin-expressing inhibitory cells and results from the independent adjustment of synapses originating from individual parvalbumin-expressing cells targeting different pyramidal cells. Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity. Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between the cortex's two opposing forces is stabilized not only in time but also in space.

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PV cell-mediated inhibition matches layer 4-mediated excitation(a) Left, schematic of experiments. Fos-EGFP, Scnn1a-Cre-Tg3 mice with ChR2 in layer 4 excitatory neurons. Right, monosynaptic EPSCs and disynaptic IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to layer 4 photoactivation. Note larger synaptic currents in EGFP+ neuron. (b–d) Summary graphs of 37 similar experiments. (b) Left, EPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between EPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. EPSC amplitudes are 40% larger in EGFP+ neurons (P = 0.0004). (c) As in (b), but for IPSCs. IPSC amplitudes are 30% larger in EGFP+ neurons (P = 0.001). (d) As in (b), but for E/I ratios. E/I ratios are similar between EGFP+ and EGFP− neurons (P = 0.7). (e) Left, schematic of experiments. Fos-EGFP, Pv-ires-Cre mice with ChR2 in PV cells. Right, IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to PV cell photoactivation. Note larger IPSC in EGFP+ neuron. (f) Summary graph. Left, IPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between IPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. IPSC amplitudes are 77% larger in EGFP+ neurons (n = 49, P = 0.001). (g, h) As in (e, f), but for Fos-EGFP, Som-ires-Cre mice with ChR2 in SOM cells. IPSC amplitudes are similar between EGFP+ and EGFP− neurons (n = 27, P = 0.7).
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Figure 2: PV cell-mediated inhibition matches layer 4-mediated excitation(a) Left, schematic of experiments. Fos-EGFP, Scnn1a-Cre-Tg3 mice with ChR2 in layer 4 excitatory neurons. Right, monosynaptic EPSCs and disynaptic IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to layer 4 photoactivation. Note larger synaptic currents in EGFP+ neuron. (b–d) Summary graphs of 37 similar experiments. (b) Left, EPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between EPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. EPSC amplitudes are 40% larger in EGFP+ neurons (P = 0.0004). (c) As in (b), but for IPSCs. IPSC amplitudes are 30% larger in EGFP+ neurons (P = 0.001). (d) As in (b), but for E/I ratios. E/I ratios are similar between EGFP+ and EGFP− neurons (P = 0.7). (e) Left, schematic of experiments. Fos-EGFP, Pv-ires-Cre mice with ChR2 in PV cells. Right, IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to PV cell photoactivation. Note larger IPSC in EGFP+ neuron. (f) Summary graph. Left, IPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between IPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. IPSC amplitudes are 77% larger in EGFP+ neurons (n = 49, P = 0.001). (g, h) As in (e, f), but for Fos-EGFP, Som-ires-Cre mice with ChR2 in SOM cells. IPSC amplitudes are similar between EGFP+ and EGFP− neurons (n = 27, P = 0.7).

Mentions: Alternatively, the correlation between excitation and inhibition could be an artifact of the slicing procedure, whereby damaged neurons receive less excitation and less inhibition. To address this possibility we used an independent marker to identify neurons receiving more excitation. We utilized Fos-EGFP mice in which the promoter of the activity-dependent immediate early gene Fos drives Fos-EGFP expression, as EGFP+ neurons receive more excitation than EGFP− neurons15. EGFP+ neurons were predominantly pyramidal cells (Extended Data Fig. 3). We photostimulated layer 4 in acute slices from Fos-EGFP, Scnn1a-Cre-Tg3 mice and simultaneously recorded pairs of EGFP+ and nearby EGFP− layer 2/3 pyramidal cells. Layer 4 activation generated larger EPSCs in EGFP+ neurons in 78% of all recorded pairs and EGFP+ neurons received, on average, 40% larger EPSCs (Fig. 2a, b, the average logarithm of EGFP+/EGFP− ratios was 0.15). Importantly, EGFP+ neurons also received larger disynaptic IPSCs (Fig. 2a, c). Consequently, the E/I ratios of EGFP+ and EGFP− neurons were similar (Fig. 2d).


Equalizing excitation-inhibition ratios across visual cortical neurons.

Xue M, Atallah BV, Scanziani M - Nature (2014)

PV cell-mediated inhibition matches layer 4-mediated excitation(a) Left, schematic of experiments. Fos-EGFP, Scnn1a-Cre-Tg3 mice with ChR2 in layer 4 excitatory neurons. Right, monosynaptic EPSCs and disynaptic IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to layer 4 photoactivation. Note larger synaptic currents in EGFP+ neuron. (b–d) Summary graphs of 37 similar experiments. (b) Left, EPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between EPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. EPSC amplitudes are 40% larger in EGFP+ neurons (P = 0.0004). (c) As in (b), but for IPSCs. IPSC amplitudes are 30% larger in EGFP+ neurons (P = 0.001). (d) As in (b), but for E/I ratios. E/I ratios are similar between EGFP+ and EGFP− neurons (P = 0.7). (e) Left, schematic of experiments. Fos-EGFP, Pv-ires-Cre mice with ChR2 in PV cells. Right, IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to PV cell photoactivation. Note larger IPSC in EGFP+ neuron. (f) Summary graph. Left, IPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between IPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. IPSC amplitudes are 77% larger in EGFP+ neurons (n = 49, P = 0.001). (g, h) As in (e, f), but for Fos-EGFP, Som-ires-Cre mice with ChR2 in SOM cells. IPSC amplitudes are similar between EGFP+ and EGFP− neurons (n = 27, P = 0.7).
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Related In: Results  -  Collection

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Figure 2: PV cell-mediated inhibition matches layer 4-mediated excitation(a) Left, schematic of experiments. Fos-EGFP, Scnn1a-Cre-Tg3 mice with ChR2 in layer 4 excitatory neurons. Right, monosynaptic EPSCs and disynaptic IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to layer 4 photoactivation. Note larger synaptic currents in EGFP+ neuron. (b–d) Summary graphs of 37 similar experiments. (b) Left, EPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between EPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. EPSC amplitudes are 40% larger in EGFP+ neurons (P = 0.0004). (c) As in (b), but for IPSCs. IPSC amplitudes are 30% larger in EGFP+ neurons (P = 0.001). (d) As in (b), but for E/I ratios. E/I ratios are similar between EGFP+ and EGFP− neurons (P = 0.7). (e) Left, schematic of experiments. Fos-EGFP, Pv-ires-Cre mice with ChR2 in PV cells. Right, IPSCs from simultaneously recorded EGFP− and EGFP+ neurons in response to PV cell photoactivation. Note larger IPSC in EGFP+ neuron. (f) Summary graph. Left, IPSC amplitudes in EGFP+ neurons plotted against those in EGFP− neurons. Right, logarithm of the ratio between IPSC amplitudes in EGFP+ and EGFP− neurons. Red: mean ± s.e.m. IPSC amplitudes are 77% larger in EGFP+ neurons (n = 49, P = 0.001). (g, h) As in (e, f), but for Fos-EGFP, Som-ires-Cre mice with ChR2 in SOM cells. IPSC amplitudes are similar between EGFP+ and EGFP− neurons (n = 27, P = 0.7).
Mentions: Alternatively, the correlation between excitation and inhibition could be an artifact of the slicing procedure, whereby damaged neurons receive less excitation and less inhibition. To address this possibility we used an independent marker to identify neurons receiving more excitation. We utilized Fos-EGFP mice in which the promoter of the activity-dependent immediate early gene Fos drives Fos-EGFP expression, as EGFP+ neurons receive more excitation than EGFP− neurons15. EGFP+ neurons were predominantly pyramidal cells (Extended Data Fig. 3). We photostimulated layer 4 in acute slices from Fos-EGFP, Scnn1a-Cre-Tg3 mice and simultaneously recorded pairs of EGFP+ and nearby EGFP− layer 2/3 pyramidal cells. Layer 4 activation generated larger EPSCs in EGFP+ neurons in 78% of all recorded pairs and EGFP+ neurons received, on average, 40% larger EPSCs (Fig. 2a, b, the average logarithm of EGFP+/EGFP− ratios was 0.15). Importantly, EGFP+ neurons also received larger disynaptic IPSCs (Fig. 2a, c). Consequently, the E/I ratios of EGFP+ and EGFP− neurons were similar (Fig. 2d).

Bottom Line: This matched inhibition is mediated by parvalbumin-expressing but not somatostatin-expressing inhibitory cells and results from the independent adjustment of synapses originating from individual parvalbumin-expressing cells targeting different pyramidal cells.Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity.Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between the cortex's two opposing forces is stabilized not only in time but also in space.

View Article: PubMed Central - PubMed

Affiliation: 1] Neurobiology Section, Division of Biological Sciences, Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, California 92093-0634, USA [2] Department of Neuroscience, University of California, San Diego, La Jolla, California 92093-0634, USA [3] Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.

ABSTRACT
The relationship between synaptic excitation and inhibition (E/I ratio), two opposing forces in the mammalian cerebral cortex, affects many cortical functions such as feature selectivity and gain. Individual pyramidal cells show stable E/I ratios in time despite fluctuating cortical activity levels. This is because when excitation increases, inhibition increases proportionally through the increased recruitment of inhibitory neurons, a phenomenon referred to as excitation-inhibition balance. However, little is known about the distribution of E/I ratios across pyramidal cells. Through their highly divergent axons, inhibitory neurons indiscriminately contact most neighbouring pyramidal cells. Is inhibition homogeneously distributed or is it individually matched to the different amounts of excitation received by distinct pyramidal cells? Here we discover that pyramidal cells in layer 2/3 of mouse primary visual cortex each receive inhibition in a similar proportion to their excitation. As a consequence, E/I ratios are equalized across pyramidal cells. This matched inhibition is mediated by parvalbumin-expressing but not somatostatin-expressing inhibitory cells and results from the independent adjustment of synapses originating from individual parvalbumin-expressing cells targeting different pyramidal cells. Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity. Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between the cortex's two opposing forces is stabilized not only in time but also in space.

Show MeSH