Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

7 figures, 3 tables and 1 additional file

Figures

Figure 1 with 5 supplements
Differential input integration at stratum oriens and stratum radiatum dendrites of PV+ interneurons.

(A) Two-photon z-projection image of a PV+ interneuron recorded via a patch pipette in stratum pyramidale (SP) and filled with Alexa-594 (left, inset: firing pattern in response to current …

https://doi.org/10.7554/eLife.49872.002
Figure 1—figure supplement 1
Somatic glutamate uncaging-evoked membrane responses.

(A) Comparison of uEPSPs to spontaneous EPSPs. Half-maximum width (ms) plotted against peak amplitude (mV) for n = 210 spontaneous events (gray) and n = 78 uEPSPs (red); data from 4 cells. Inset: …

https://doi.org/10.7554/eLife.49872.003
Figure 1—figure supplement 2
Unscaled uEPSP integration location-dependent nonlinearity.

Comparisons of the arithmetic sum of individual uEPSPs and corresponding recorded uEPSPs evoked at locations in stratum radiatum (blue, n = 9) and stratum oriens (red, n = 14). (A, B) Unscaled uEPSP …

https://doi.org/10.7554/eLife.49872.004
Figure 1—figure supplement 3
uEPSP integration location-dependent nonlinearity by cell.

(A) Peak amplitude nonlinearity comparison by dendrite location. Statistics for all data, oriens vs radiatum: 26.0 ± 6.0% (n = 9) vs 5.4 ± 5.4% (n = 8), p=0.02. Statistics for paired data oriens vs …

https://doi.org/10.7554/eLife.49872.005
Figure 1—figure supplement 4
uEPSP nonlinearity does not depend on uncaging location distance from soma or on the size of the arithmetic sum of uEPSPs.

(A) uEPSP amplitude nonlinearity plotted against glutamate uncaging site distance from soma. (B) uEPSP amplitude nonlinearity plotted against maximal arithmetic sum of uEPSP amplitudes. (C) As (A) …

https://doi.org/10.7554/eLife.49872.006
Figure 1—figure supplement 5
Compound uEPSPs from uncaging locations clustered on a single dendrite display larger nonlinearities than when distributed across two dendrites.

(A) Top: Two-photon z-stack of PV+ interneuron in CA1 region of hippocampus. White box marks region of interest shown below. Scale bar: 50 µm. Bottom: dendritic regions of interest at higher …

https://doi.org/10.7554/eLife.49872.007
Figure 2 with 2 supplements
NMDARs mediate stratum oriens dendrite synaptic integration supralinearity.

(A) Two-photon z-stack of PV+ interneuron in CA1 region of hippocampus. Red box marks glutamate uncaging location. (B) Comparison of arithmetic and recorded uEPSP summation waveforms in the presence …

https://doi.org/10.7554/eLife.49872.008
Figure 2—figure supplement 1
Peak amplitude nonlinearity in oriens dendrites is abolished by blocking NMDARs with D-AP5 but not by blocking sodium channels with TTX.

(A) Summary scaled peak amplitude uEPSP data for 14 dendritic locations recorded in D-AP5, n = 10 oriens; n = 4 radiatum. Right: quantified synaptic integration nonlinearity. Oriens vs radiatum: 1.9 …

https://doi.org/10.7554/eLife.49872.009
Figure 2—figure supplement 2
Arithmetic sum maximum uEPSP amplitudes, and integration nonlinearity vs uncaging location distances, across pharmacological conditions.

(A – C) Peak arithmetic uEPSP amplitudes by uncaging dendrite location in control conditions (A, replotted from Figure 1—figure supplement 1B for comparison), D-AP5 (B), and TTX (C). (D – F) uEPSP …

https://doi.org/10.7554/eLife.49872.010
Figure 3 with 1 supplement
Differential NMDAR expression and dendrite morphology explain stratum-dependent synaptic integration difference.

(A) Schematic describing stimulation of feedforward (S1, blue) and antidromic stimulation of feedback (S2, red) axons. Middle: example paired AMPAR and NMDAR EPSC components in low [Mg2+]. Right: …

https://doi.org/10.7554/eLife.49872.011
Figure 3—figure supplement 1
Simulations including polyamine modulation of AMPARs show synaptic integration differences between strata oriens and radiatum dendrite locations.

(A) Scaled recorded time-integrals vs scaled arithmetic sum of time-integrals at all locations with equal NMDAR conductance (oriens locations: n = 28, radiatum locations: n = 16). As Figure 3D, but …

https://doi.org/10.7554/eLife.49872.012
NMDAR recruitment at CA1 pyramidal cell feedback connections onto PV+ interneurons.

(A) Schematic of viral injections into dorsal CA1 of PV-tdTomato mice (left), and confocal image of a sagittal hippocampal slice showing selective ChR2-EYFP expression in CA1 pyramidal cells …

https://doi.org/10.7554/eLife.49872.013
Figure 5 with 2 supplements
Network architecture and NMDAR recruitment at feedback connections.

(A) Schematic of network structure. (B) Voltage traces of interneuron (black) and principal cells (blue, cell # at right) during network simulation. The network was driven by an asynchronous barrage …

https://doi.org/10.7554/eLife.49872.014
Figure 5—figure supplement 1
Modeling principal cell input cooperation onto feedback interneurons.

(A) Network schematic showing postsynaptic membrane locations of Izhikevich-model PV+ interneuron. (B) Steady state transfer resistance for a PV+ cell dendritic tree reconstructed using the TREES …

https://doi.org/10.7554/eLife.49872.015
Figure 5—figure supplement 2
NMDARs help to maintain a sparse and sharp representation of a ‘hump’ of excitation to the feedback circuit shown in Figure 5D.

(A) Distribution of firing rate by neuron during each PV+ interneuron firing cycle, averaged across 500 simulations. Top – without NMDARs, bottom – with NMDARs. The hump of excitation was centered …

https://doi.org/10.7554/eLife.49872.016
The role of NMDARs at feedback connections in cell assembly competition.

(A) Right: schematic showing competing cell assemblies with clustered (blue) or dispersed (orange) inputs; left: example simulation of lateral inhibition between these subnetworks with NMDARs at …

https://doi.org/10.7554/eLife.49872.017
Figure 7 with 1 supplement
The role of NMDARs at feedback connections in cell assembly stability.

(A) Cartoon illustrating a bistable neural representation. (B) Schematic of competing subnetworks both receiving clustered inputs (left) with random fluctuations in external input strength (plotted …

https://doi.org/10.7554/eLife.49872.018
Figure 7—figure supplement 1
The role of NMDARs at feedback connections in cell assembly stability with theta-modulated external drive.

(A) Theta-modulated external drive to the system. (B) Example simulation of network with NMDARs at synapses on interneurons (top), and with NMDARs scaled down to 25% of baseline (bottom). External …

https://doi.org/10.7554/eLife.49872.019

Tables

Key resources table
Reagent type (species)
or resource
DesignationSource or referenceIdentifiersAdditional information
Strain, strain background (Mus musculus)B6;129P2-Pvalbtm1(cre)Arbr/JThe Jackson Laboratory008069
Strain, strain background (Mus musculus)B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)HzeThe Jackson Laboratory007909
OtherAAV5-CaMKIIa-hChR2(H134R)-EYFPUNC Vector Core
Chemical compound, drugPicrotoxinSigma-AldrichP1675
Chemical compound, drugCGP 55845AbcamAb120337
Chemical compound, drugD-AP5Tocris0105
Chemical compound, drugTTXTocris1078
Chemical compound, drugZD 7288Tocris1000
Chemical compound, drugMNI-glutamate TFAFemtonics1951
Table 1
NEURON model parameters.
https://doi.org/10.7554/eLife.49872.020
ParameterProximalDistalUnits
Cm0.90.9µF cm-2
Raxial170170Ω cm
Rm5.5555.5
eleak-65-mV
egk-90-mV
egNa55-mV
v Shift-12-12mV
gk dend300300pS µm-2
gNa dend200100pS µm-2
gNa Soma2000-pS µm-2
Table 2
model neuron parameters for network modeling.
https://doi.org/10.7554/eLife.49872.021
ParameterFS PV+PyramidalUnits
Cm90115pF
klow1.70.1nS/mV
khigh143.3nS/mV
vr−60.6−65.8mV
vpeak 2.522.6mV
vt−43.1−57mV
a0.10.0012ms−1
b−0.13nS
c−67−65.8mV
d0.110pA
τ1AMPA0.250.2ms
τ2AMPA0.771.7ms
τ1GABA0.270.3ms
τ2GABA1.73.5ms
τ1NMDA2-ms
τ2NMDA60-ms
eglu00mV
eGABA−70−70mV
σD20.015/(npyr2)--
Csyn9-pF
ksyn3/npyr--
gleak5-nS
eleak−60.6-mV
kAMPA28--
kNMDA212--
kGABA2827-
kext51-
  1. Izhikevich Parameter values as in Ferguson et al. (2014) and Ferguson et al. (2013). Synaptic time constants: (Bartos et al., 2002; Geiger et al., 1997; Roth and van Rossum, 2009). Remaining parameters where adjusted to allow the network to generate a gamma rhythm.

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