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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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Overexpression of Kir2.1 increases a Ba2+-sensitive K+ current and decreases neuronal excitability(a) Schematics of experiments. Kir2.1 or a non-conducting mutant Kir2.1 (Kir2.1Mut) was overexpressed in a subset of layer 2/3 pyramidal cells by in utero electroporation. (b) Membrane currents in response to a 5-s membrane potential ramp from −25 mV to −125 mV from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. The purple traces were recorded in control condition and the grey traces were recorded in the presence of 50 μM BaCl2. The blue traces were obtained by subtracting the grey traces from the purple traces, representing the Ba2+-blocked K+ currents. At the concentration of 50 μM, Ba2+ primarily blocks the K+ channels of the Kir2 subfamily49. (c) The exogenously overexpressed Kir2.1 increased not only the Ba2+-blocked inward current density at −125 mV (P = 0.01), but also the outward current density at −45 mV (P = 0.001) due to its reduced inward rectification (see Methods). (d) Kir2.1Mut can bind to the endogenous Kir2.1 to form non-conducting channels49, acting as a dominant negative to decrease the inward current density at −125 mV (P = 0.004) but without affecting the outward current density at −45 mV (P = 0.2). (e) Membrane potentials (upper panels) in response to current injections (lower panels) from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. (f–h) Overexpression of Kir2.1 hyperpolarized the resting membrane potential (f, P = 0.0003), decreased the resting input resistance (g, P < 0.0001), and increased the rheobase current (h, P < 0.0001). (i–k) Overexpression of Kir2.1Mut increased the resting input resistance (j, P = 0.0002), but had no effects on the resting membrane potential (i, P = 0.5) and the rheobase current (k, P = 0.9). The numbers of recorded neurons are indicated on the bars. All data are expressed as mean ± s.e.m.
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Figure 9: Overexpression of Kir2.1 increases a Ba2+-sensitive K+ current and decreases neuronal excitability(a) Schematics of experiments. Kir2.1 or a non-conducting mutant Kir2.1 (Kir2.1Mut) was overexpressed in a subset of layer 2/3 pyramidal cells by in utero electroporation. (b) Membrane currents in response to a 5-s membrane potential ramp from −25 mV to −125 mV from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. The purple traces were recorded in control condition and the grey traces were recorded in the presence of 50 μM BaCl2. The blue traces were obtained by subtracting the grey traces from the purple traces, representing the Ba2+-blocked K+ currents. At the concentration of 50 μM, Ba2+ primarily blocks the K+ channels of the Kir2 subfamily49. (c) The exogenously overexpressed Kir2.1 increased not only the Ba2+-blocked inward current density at −125 mV (P = 0.01), but also the outward current density at −45 mV (P = 0.001) due to its reduced inward rectification (see Methods). (d) Kir2.1Mut can bind to the endogenous Kir2.1 to form non-conducting channels49, acting as a dominant negative to decrease the inward current density at −125 mV (P = 0.004) but without affecting the outward current density at −45 mV (P = 0.2). (e) Membrane potentials (upper panels) in response to current injections (lower panels) from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. (f–h) Overexpression of Kir2.1 hyperpolarized the resting membrane potential (f, P = 0.0003), decreased the resting input resistance (g, P < 0.0001), and increased the rheobase current (h, P < 0.0001). (i–k) Overexpression of Kir2.1Mut increased the resting input resistance (j, P = 0.0002), but had no effects on the resting membrane potential (i, P = 0.5) and the rheobase current (k, P = 0.9). The numbers of recorded neurons are indicated on the bars. All data are expressed as mean ± s.e.m.

Mentions: We reduced the excitability of a small, random subset of layer 2/3 pyramidal cells in V1 by overexpressing a Kir2.1 channel via in utero electroporation20–22 (Fig. 3a). Recordings in acute slices confirmed the reduced excitability in Kir2.1-overexpressing cells (Kir2.1 neurons) as compared to untransfected control pyramidal cells (Extended Data Fig. 4). In vivo targeted recordings from Kir2.1 and nearby control neurons (Fig. 3b, c) demonstrated that Kir2.1 overexpression drastically suppressed visual-evoked and spontaneous activity (Fig. 3d–f). We then examined the impact of this perturbation on excitation and inhibition. We photostimulated layer 4 and simultaneously recorded Kir2.1 and neighboring control neurons in the acute slices from Scnn1a-Cre-Tg3 mice. Surprisingly, layer 4-mediated excitation was not significantly different between these two groups (Fig. 3g, h), invalidating the first aforementioned possibility. In contrast, disynaptic inhibition was significantly smaller in Kir2.1 neurons (Fig. 3g, i), consistent with the second possibility. The effect on inhibition was due to the channel function of Kir2.1 because a non-conducting Kir2.1 mutant (Extended Data Fig 4) had no effect (Extended Data Fig. 5). Thus, perturbing layer 2/3 pyramidal cell excitability disrupts the proportionality between excitation and inhibition (Fig. 3j). These data indicate that pyramidal cell activity contributes to the equalization of E/I ratios across pyramidal cells.


Equalizing excitation-inhibition ratios across visual cortical neurons.

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

Overexpression of Kir2.1 increases a Ba2+-sensitive K+ current and decreases neuronal excitability(a) Schematics of experiments. Kir2.1 or a non-conducting mutant Kir2.1 (Kir2.1Mut) was overexpressed in a subset of layer 2/3 pyramidal cells by in utero electroporation. (b) Membrane currents in response to a 5-s membrane potential ramp from −25 mV to −125 mV from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. The purple traces were recorded in control condition and the grey traces were recorded in the presence of 50 μM BaCl2. The blue traces were obtained by subtracting the grey traces from the purple traces, representing the Ba2+-blocked K+ currents. At the concentration of 50 μM, Ba2+ primarily blocks the K+ channels of the Kir2 subfamily49. (c) The exogenously overexpressed Kir2.1 increased not only the Ba2+-blocked inward current density at −125 mV (P = 0.01), but also the outward current density at −45 mV (P = 0.001) due to its reduced inward rectification (see Methods). (d) Kir2.1Mut can bind to the endogenous Kir2.1 to form non-conducting channels49, acting as a dominant negative to decrease the inward current density at −125 mV (P = 0.004) but without affecting the outward current density at −45 mV (P = 0.2). (e) Membrane potentials (upper panels) in response to current injections (lower panels) from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. (f–h) Overexpression of Kir2.1 hyperpolarized the resting membrane potential (f, P = 0.0003), decreased the resting input resistance (g, P < 0.0001), and increased the rheobase current (h, P < 0.0001). (i–k) Overexpression of Kir2.1Mut increased the resting input resistance (j, P = 0.0002), but had no effects on the resting membrane potential (i, P = 0.5) and the rheobase current (k, P = 0.9). The numbers of recorded neurons are indicated on the bars. All data are expressed as mean ± s.e.m.
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Related In: Results  -  Collection

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Figure 9: Overexpression of Kir2.1 increases a Ba2+-sensitive K+ current and decreases neuronal excitability(a) Schematics of experiments. Kir2.1 or a non-conducting mutant Kir2.1 (Kir2.1Mut) was overexpressed in a subset of layer 2/3 pyramidal cells by in utero electroporation. (b) Membrane currents in response to a 5-s membrane potential ramp from −25 mV to −125 mV from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. The purple traces were recorded in control condition and the grey traces were recorded in the presence of 50 μM BaCl2. The blue traces were obtained by subtracting the grey traces from the purple traces, representing the Ba2+-blocked K+ currents. At the concentration of 50 μM, Ba2+ primarily blocks the K+ channels of the Kir2 subfamily49. (c) The exogenously overexpressed Kir2.1 increased not only the Ba2+-blocked inward current density at −125 mV (P = 0.01), but also the outward current density at −45 mV (P = 0.001) due to its reduced inward rectification (see Methods). (d) Kir2.1Mut can bind to the endogenous Kir2.1 to form non-conducting channels49, acting as a dominant negative to decrease the inward current density at −125 mV (P = 0.004) but without affecting the outward current density at −45 mV (P = 0.2). (e) Membrane potentials (upper panels) in response to current injections (lower panels) from an untransfected control pyramidal cell, a pyramidal cell overexpressing Kir2.1, and a pyramidal cell overexpressing Kir2.1Mut. (f–h) Overexpression of Kir2.1 hyperpolarized the resting membrane potential (f, P = 0.0003), decreased the resting input resistance (g, P < 0.0001), and increased the rheobase current (h, P < 0.0001). (i–k) Overexpression of Kir2.1Mut increased the resting input resistance (j, P = 0.0002), but had no effects on the resting membrane potential (i, P = 0.5) and the rheobase current (k, P = 0.9). The numbers of recorded neurons are indicated on the bars. All data are expressed as mean ± s.e.m.
Mentions: We reduced the excitability of a small, random subset of layer 2/3 pyramidal cells in V1 by overexpressing a Kir2.1 channel via in utero electroporation20–22 (Fig. 3a). Recordings in acute slices confirmed the reduced excitability in Kir2.1-overexpressing cells (Kir2.1 neurons) as compared to untransfected control pyramidal cells (Extended Data Fig. 4). In vivo targeted recordings from Kir2.1 and nearby control neurons (Fig. 3b, c) demonstrated that Kir2.1 overexpression drastically suppressed visual-evoked and spontaneous activity (Fig. 3d–f). We then examined the impact of this perturbation on excitation and inhibition. We photostimulated layer 4 and simultaneously recorded Kir2.1 and neighboring control neurons in the acute slices from Scnn1a-Cre-Tg3 mice. Surprisingly, layer 4-mediated excitation was not significantly different between these two groups (Fig. 3g, h), invalidating the first aforementioned possibility. In contrast, disynaptic inhibition was significantly smaller in Kir2.1 neurons (Fig. 3g, i), consistent with the second possibility. The effect on inhibition was due to the channel function of Kir2.1 because a non-conducting Kir2.1 mutant (Extended Data Fig 4) had no effect (Extended Data Fig. 5). Thus, perturbing layer 2/3 pyramidal cell excitability disrupts the proportionality between excitation and inhibition (Fig. 3j). These data indicate that pyramidal cell activity contributes to the equalization of E/I ratios across pyramidal cells.

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