1. Neuroscience

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

  1. Javier Zorrilla de San Martin  Is a corresponding author
  2. Cristina Donato
  3. Jérémy Peixoto
  4. Andrea Aguirre
  5. Vikash Choudhary
  6. Angela Michela De Stasi
  7. Joana Lourenço
  8. Marie-Claude Potier  Is a corresponding author
  9. Alberto Bacci  Is a corresponding author
  1. Institut du Cerveau (ICM), CNRS UMR 7225 – Inserm U1127, Sorbonne Université, France
https://doi.org/10.7554/eLife.58731
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Cite this article
  1. Javier Zorrilla de San Martin
  2. Cristina Donato
  3. Jérémy Peixoto
  4. Andrea Aguirre
  5. Vikash Choudhary
  6. Angela Michela De Stasi
  7. Joana Lourenço
  8. Marie-Claude Potier
  9. Alberto Bacci
(2020)
Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome
eLife 9:e58731.
https://doi.org/10.7554/eLife.58731
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7 figures, 14 tables and 1 additional file

Figures

Figure 1 with 3 supplements
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Synaptic enhancement of dendritic inhibition in DS.

(a) Schematic of cortical inhibitory circuits involving PV interneurons, MCs and PNs. (b) Representative voltage-clamp current traces of uIPSCs recorded in MC-PN connected pair in a Eu (top) and a …

Figure 1—source data 1

Synaptic properties of the dendritic inhibitory loop.

https://cdn.elifesciences.org/articles/58731/elife-58731-fig1-data1-v2.xlsx
Figure 1—figure supplement 1
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GFP positive interneurons in the prefrontal cortex of Ts::X98 mice are Martinotti cells.

(a) Immunostaining using anti-GFP (green) and anti-SST (red) antibodies in the mPFC. Note the co-localization of both markers. Arrows point to GFP and SST. (b) Biocytin-filled GFP-positive …

Figure 1—figure supplement 2
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Abnormal IPSC kinetics in DS.

(a) Representative unitary inhibitory synaptic currents recorded at the MC to PN synapse. Inset: detail of the rise phase. (b) Population data of the rise time (left, p=0.02448, Mann-Whitney U test) …

Figure 1—figure supplement 2—source data 1

MC to PN synapse kinetics.

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Figure 1—figure supplement 3
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Short term plasticity of the dendritic inhibitory loop in Ts.

(a) Schematic representation of the inhibitory synapse of the cortical dendritic inhibitory loop mediated by MCs. (b) Normalized amplitude of IPSCs evoked by a 5-AP train applied at 50 Hz to the …

Figure 1—figure supplement 3—source data 1

Short term plasticity of the dendritic inhibitory loop.

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Figure 2 with 3 supplements
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Normal excitability and morphology of PNs and MCs in Ts mice.

(a) Representative current-clamp traces of membrane potential responses to injections of current steps of increasing amplitude applied to PNs (above) and MCs (below) from Eu (gray) and Ts (blue) …

Figure 2—source data 1

Excitability and morphology of PNs and MCs.

https://cdn.elifesciences.org/articles/58731/elife-58731-fig2-data1-v2.xlsx
Figure 2—figure supplement 1
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Single action potential and passive properties are normal Ts mPFC PNs.

(a) AP thresholds estimated as the voltage at which the derivative of Vm as function of time (dV/dt) reaches the limit of 10 mV/ms. Eu: −41 mV, −45–39 mV (n = 23 cells) and Ts: −40, −41–39 mV mV (n =…

Figure 2—figure supplement 1—source data 1

Singleaction potentialand passive properties of mPFC PNs.

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Figure 2—figure supplement 2
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Active and passive properties are normal in mPFC MCs from Ts65Dn mice.

(a) AP thresholds estimated as the voltage at which the derivative of Vm as function of time (dV/dt) reaches the limit of 10 mV/ms. Eu: −46, −52–42 (n = 23 cells); Ts: −43, −45–42 (n = 25 cells, …

Figure 2—figure supplement 2—source data 1

Singleaction potentialand passive properties of mPFC MCs.

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Figure 2—figure supplement 3
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Normal SST-positive interneurons density in the mPFC of Ts mice.

(a) Representative fluorescence micrographs illustrating SST (red, left) and GFP (green, middle) immunostaining in Eu and Ts mice. Right column: merge of red and green channel (b) Quantification of …

Figure 3 with 1 supplement
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Perisomatic inhibition by PV-INs is normal in Ts mice.

(a) Left: scheme of the PV-PN perisomatic inhibitory circuit assessed using dual whole-cell patch-clamp recordings. Right: representative voltage-clamp traces corresponding to uIPSCs evoked upon …

Figure 3—source data 1

Synaptic properties of the perisomatic inhibitory loop.

https://cdn.elifesciences.org/articles/58731/elife-58731-fig3-data1-v2.xlsx
Figure 3—figure supplement 1
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Short term plasticity of the perisomatic inhibitory loop in Ts.

(a) Schematic representation of the inhibitory synapse of the cortical dendritic inhibitory loop mediated by MCs. (b) Normalized amplitude of IPSCs evoked by a 5-AP train applied at 50 Hz to the …

Figure 3—figure supplement 1—source data 1

Short term plasticity of the perisomatic inhibitory loop in Ts.

https://cdn.elifesciences.org/articles/58731/elife-58731-fig3-figsupp1-data1-v2.xlsx
Figure 4 with 2 supplements
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Altered excitability of PV cells in Ts mice.

(a) Representative voltage traces in response to current steps of increased amplitudes applied to to PV-INs from Eu (gray) and Ts (blue). (b) Representative F-I curves recorded from Eu (top) and Ts …

Figure 4—source data 1

Excitability of PV cells.

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Figure 4—figure supplement 1
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Specific alteration of mPFC PV-INs electrical properties in Ts65Dn mice.

(a) AP thresholds estimated as the voltage at which the derivative of Vm as function of time (dV/dt) reaches the limit of 10 mV/ms. Eu: −43 mV −47-−39 (n = 26 cells), Ts: −44 mV −46-−41 (n = 26 …

Figure 4—figure supplement 1—source data 1

Singleaction potentialand passive properties of mPFC PV cells.

https://cdn.elifesciences.org/articles/58731/elife-58731-fig4-figsupp1-data1-v2.xlsx
Figure 4—figure supplement 2
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PV cells passive and active properties as function of Age.

Passive properties plotted as a function of age during the developmental period under study. (a) Resting membrane potential (Vrest). (b) Input Resistance (Ri). (c) Membrane time constant (Tau …

Figure 5 with 1 supplement
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Reduced spiking activity in vivo and increased tuning with network oscillations in anesthetized Ts65Dn mPFC.

(a) Left: scheme depicting simultaneous local field potential (LFP) and juxtacellular recordings in layer 2/3 of the mPFC. Right: representative juxtacellular (top trace), LFP (middle trace) and …

Figure 5—source data 1

In vivo spiking activity and phase locking.

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Figure 5—figure supplement 1
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Characterization of slow wave oscillatory activity of LFP in anesthetized Eu and Ts mice.

(a) Representative LFP traces of anesthetized Eu (black, top) and Ts (bottom, blue) mice. (b) Histograms of UP states duration from the examples shown in (a) Eu (gray bars) and Ts (blue bars) …

Author response image 1
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Author response image 2
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Tables

Table 1
MC to PN synaptic efficiency evaluation.
Dendritic Inhibition
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
MC-PN IPSCAmplitude (pA)29.8920.2452.981197.0954.49135.8615MW-test0.0095
Failure Rate0.200.110.25110.000.000.1315MW-test0.0201
Charge (pC)1.280.961.84116.862.968.3215MW-test0.00595
α5IA % block4124.2057.20457.433.1073.106MW-test0.2278
Rise Time (ms)1.201.001.80181.701.502.1018MW-test0.02448
Decay Time (ms)15.6010.0019.401817.1015.0021.7018MW-test0.1488

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; IPSC: Inhibitory postsynaptic current.

Table 2
PN to MC synaptic efficiency evaluation.
Dendritic Inhibition
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
PN-MC EPSCAmplitude (pA)5.362.137.46718.6611.4428.217T-test0.0106
Failure Rate0.870.810.9370.520.390.717MW-test0.0126
Charge (pC)0.270.220.3170.870.531.137MW-test0.0073

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; EPSC: Excitatory postsynaptic current.

Table 3
PNs excitability.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
ExcitabilityInjCurr50 (pA)21.619.524.41218.915.924.611T-test0.6081
Max Spiking Rate (Hz)112.491.9155.012124.5101.0178.211T-test0.4500

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; InjCurr50: amount of current injected to reach 50% of the maximal spiking rate.

Table 4
MCs excitability.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
ExcitabilityInjCurr50 (pA)40.926.950.42548.925.470.220MW-test0.6073
Max Spiking Rate (Hz)101.868.3124.02586.563.2109.720T-test0.4436

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; InjCurr50: amount of current injected to reach 50% of the maximal spiking rate.

Table 5
PNs passive and action potential (AP) properties.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
Passive propertiesVrest (mV)-76-79-7225-73-78-6922T-test0.2473
Ri (MΩ)255139378251788631622T-test0.7185
Tau memb (ms)36.528.147.92539.726.846.922T-test0.5790
AP propertiesThreshold (mV)-40.9-45.6-39.225-39.6-40.8-38.522MW-test0.0453
Amplitude (mV)83.675.185.82582.569.285.522MW-test0.3749
Width (ms)1.21.01.6251.21.01.622MW-test0.7413

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; Vrest: Resting membrane potential; Ri : input resistance.

Table 6
MCs passive and action potential (AP) properties.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
Passive propertiesVrest (mV)-66-70-6326-64-67-6220T-test0.0566
Ri (MΩ)2381833822620717628220MW-test0.5721
Tau memb (ms)27.022.441.42533.028.751.720MW-test0.1407
AP propertiesThreshold (mV)79.063.285.12683.477.388.520MW-test0.0988
Amplitude (mV)-45.8-51.5-42.226-42.9-44.6-42.020MW-test0.0727
Width (ms)1.20.91.6261.20.91.520MW-test0.8680

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; Vrest: Resting membrane potential ; Ri : input resistance.

Table 7
Direct perisomatic inhibition.

PV to PN synaptic efficiency evaluation.

Perisomatic inhibition
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
PV-PN IPSCAmplitude (pA)188.4374.87289.0326144.5246.10209.7815MW-test0.49
Failure Rate0.000.000.03260.000.000.0015MW-test0.7185
Charge (pC)2.881.925.02264.891.895.8515MW-test0.579

  1. PV to PN synaptic efficiency evaluation. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; IPSC: Inhibitory postsynaptic current.

Table 8
Recruitment of PV-INs by PNs.

PN to PV synaptic efficiency evaluation.

Perisomatic inhibition
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
PN-PVEPSCAmplitude (pA)65.6619.28124.501520.4114.1084.259MW-test0.23304
Failure Rate0.000.000.27150.130.000.579MW-test0.21402
Charge (pC)0.620.290.90150.420.200.559MW-test0.3711

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; EPSC: Excitatory postsynaptic current.

Table 9
PV-INs excitability.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
ExcitabilityRheobase (pA)198.7104.1276.71954.434.698.726MW0.0004
Gain (Hz)163.234.6233.81928.220.244.226MW0.0004
Max Spiking Rate (Hz)99.545.2142.31947.945.363.326MW0.0001

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; InjCurr50: amount of current injected to reach 50% of the maximal spiking rate.

Table 10
PV-INs passive and action potential (AP) properties.
EuploidTs65Dn
medianQ1Q3nmedianQ1Q3ntestp value
Passive propertiesVrest (mV)-71-75-6928-70-71-6626T-test0.1808
Ri (MΩ)154932712840626458126MW-test0.0001
Tau memb (ms)12.06.520.62825.820.237.325MW-test0.0003
AP propertiesThreshold (mV)-43.4-47.0-39.526-44.0-46.0-41.326T-test0.7891
Amplitude (mV)65.254.670.32569.062.873.425T-test0.1019
Width (ms)0.80.71.3261.31.01.626MW-test0.0012

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells; Vrest: Resting membrane potential; Ri : input resistance.

Table 11
LFP and single cell spiking recorded in vivo.
EuploidTs65Dn
medianQ1Q3N cellsN micemedianQ1Q3N cellsN micetestp value
Spiking Rate (Hz)0.810.561.242860.420.220.92235MW-test0.0348
stLFPpeak-to-peak Amp (µV)7.36.08.622613.312.317.1115MW-test0.0011

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells.

Table 12
Pairwise Phase Consistency (PPC) descriptive statistics and hypothesis tests between genotypes for each frequency band analyzed.
EuploidTs65Dn
Freq. bandmedianQ1Q3N cellsN micemedianQ1Q3N cellsN micetestp value
PPC4-10 Hz0.00850.00530.02422260.01060.00640.0164115MW-test0.4270
10-20 Hz0.00460.00110.02372260.02130.01630.0379115MW-test0.0215
20-40 Hz0.0024-0.00020.00852260.00660.00590.0193115MW-test0.0418
40-60 Hz0.0009-0.00090.00252260.00520.00190.0079115MW-test0.0164
60-80 Hz-0.0003-0.00070.00042260.0001-0.00050.0009115MW-test0.2308
80-100 Hz-0.0002-0.00090.0013226-0.0004-0.00080.0002115MW-test0.3161

  1. Median: quantile 50; Q1: quantile 25; Q3: quantile 75; n: number of cells. We considered only cells from which we recorded at least 250 action potentials in order to obtain reliable PPC values.

Key resources table
Reagent type
(species) or resource		DesignationSource or referenceIdentifiersAdditional information
Genetic reagent (M. musculus)C57BL/6-Tg(Pvalb-tdTomato)15Gfng/J (PValb-Tomato)Jackson LaboratoryStock #: 27395
RRID:MGI:5629295
Genetic reagent (M. musculus)Tg(Gad1-EGFP)98Agmo/J, GAD67-GFP (X98)Jackson LaboratoryStock #: 6340
RRID:MGI:3715263
Genetic reagent (M. musculus)B6EiC3Sn.BLiA-Ts(1716)65Dn/DnJ (Ts65Dn)Jackson LaboratoryStock #: 005252
RRID:MGI:2178111
Author response table 1
Eu (n = 8) P23-25Ts (n = 10) P23-25P value*Kaiser et al. 2016§ P45-90
Ri (MΩ)94.6 ± 6.7200.3 ± 45.3p = 0.0034119 ± 4.0
τm (ms)6.9 ± 0.925.7 ± 4.2p = 0.00047.2 ± 0.2
AP width (ms)0.66 ± 0.031.44 ± 0.20p = 0.00260.5 ± 0.01

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