The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs

  1. Ryan S Phillips
  2. Ian Rosner
  3. Aryn H Gittis
  4. Jonathan E Rubin  Is a corresponding author
  1. Department of Mathematics, University of Pittsburgh, United States
  2. Center for the Neural Basis of Cognition, United States
  3. Department of Biological Sciences, Carnegie Mellon University, United States
14 figures, 1 table and 1 additional file

Figures

Two-compartment SNr model neuron includes currents that affect [Cl-]i and produces appropriate dynamics.

(A) Schematic diagram of the model. (B) Tonic spiking voltage traces for both compartments, with minimum voltages labeled. (C) Model f-I curve. (D) Phase plot of the rate of change of the membrane …

Simulated short-term synaptic depression and facilitation of GABAergic synapses originating from GPe neurons of the indirect pathway (A and B) and Str neurons of the direct pathway (C and D) under voltage clamp.

For the GPe and Str simulations, the left traces (A and C) show current and right panels (B and D) show the pared pulse ratios (PPR) resulting from repeated synaptic stimulation at different …

Simulated short-term synaptic depression and facilitation of GABAergic synapses originating from GPe neurons of the indirect pathway (A and B) and Str neurons of the direct pathway (C and D) under current clamp.

For the GPe and Str simulations, the left traces (A and C) show voltage and right panels (B and D) show the pared pulse ratios (PPR) resulting from repeated synaptic stimulation at different …

Figure 4 with 1 supplement
Tonic chloride conductance and extrusion capacity determine somatic EGABA and SNr responses to simulated 40 Hz GPe stimulation.

(A) Dependence of somatic EGABA on the tonic chloride conductance (gGABATonic) and the potassium-chloride co-transporter KCC2 extrusion capacity (gKCC2). (B–E) Examples of SNr responses to simulated indirect …

Figure 4—figure supplement 1
Biphasic SNr response to longer simulated GPe stimulation.

(A) Dependence of somatic EGABA on the tonic chloride conductance (gGABATonic) and the potassium-chloride co-transporter KCC2 extrusion capacity (gKCC2) as previously shown in Figure 4A. (B) Example of ‘Partial …

Tonic chloride conductance and extrusion capacity determine dendritic EGABA and SNr responses to 20 Hz Str stimulation.

(A) Dependence of somatic EGABA on the tonic chloride conductance (gGABATonic) and the potassium-chloride co-transporter KCC2 extrusion capacity (gKCC2). (B–F) Examples of SNr responses to simulated indirect …

Figure 6 with 2 supplements
Characterization of experimentally observed SNr responses to optogenetic stimulation of (top) GPe and (bottom) Str projections to SNr in vitro.

(A1 and B1) Examples of response types observed for 10 s stimulation of GPe or Str projections. (A2 and B2) Quantification types of SNr response to optogenetic stimulation at varying frequencies …

Figure 6—figure supplement 1
Summary of SNr responses to optogenetic stimulation of GPe synaptic terminals.

(A1–A4) Raster plots of spiking sorted by the duration of the pause in spiking at the start of the stimulation period for all SNr neurons tested. (B1–B4) Effect of GPe stimulation on the firing rate …

Figure 6—figure supplement 2
Summary of SNr responses to optogenetic stimulation of Str synaptic terminals.

(A1–A4) Raster plots of spiking sorted by the duration of the pause in spiking at the start of the stimulation period for all SNr neurons tested. (B1–B4) Effect of Str stimulation on the firing rate …

Phase response curves (PRCs) of the model SNr neuron depend on EGABA.

(A and B) Example traces illustrating the effect of a single GABAergic synaptic input on the phase of spiking in a simulated SNr neuron for hyperpolarized and depolarized EGABA, respectively. (C) For …

Figure 8 with 1 supplement
Effect of EGABA on SNr synchrony in a unidirectional (left) and bidirectional (right) synaptically connected two-neuron network.

(A1-A3 and B1-B3) (Top) Identification of PRC fixed points and (Bottom) histogram of the timing of synaptic inputs in the phase of neuron 2 (Input Phase) as a function of EGABA. Recall that positive …

Figure 8—figure supplement 1
Schematic illustration of the convergence toward anti-phase locking in a birectionally coupled pair of SNr neurons.

Each vertical, deeply colored bar denotes a spike time of the cell with that color (red or blue). Following the spike time of each cell, the PRC for that cell is shown (the PRCs for EGABA=-60mV are used). …

Characterization of phase slipping oscillations in the unidirectionally connected two-neuron network.

(A) Illustration of the phase of the postsynaptic neuron at the moment when it receives each input from the presynaptic neuron (input phase) for the unidirectionally connected two neuron network as …

Figure 10 with 7 supplements
Effects of changing the presynaptic firing rate on synchrony and postsynaptic oscillations in a feed-forward SNr neuron pair.

(A) Tuning curve for presynaptic firing rate (FR) versus applied current, IAPP. Dashed line indicates the baseline firing rate (10.5 Hz) with no applied current. (B) Histograms of the input phase in …

Figure 10—figure supplement 1
The relationship between EGABA and phase locking and the emergence of slow oscillations are maintained at least up to in vivo SNr firing rates.

(A) Relationship between applied current (IAPP) and the firing rate of an isolated SNr model neuron. (B) Example voltage trace for a simulated neuron firing at 33.0 Hz with IAPP=0.8pA/pF. (C) Histograms of input …

Figure 10—figure supplement 2
Effect of increasing noise on SNr phase relationships as a function of EGABA.

(A) Dependence of CV (blue) and firing rate (red) of model SNr neuron on applied noise amplitude. (B) Example voltage trace at the highest level of added Gaussian noise (0.6pA/pF) and CV=0.1. (C) …

Figure 10—figure supplement 3
Effect of synaptic delay on the relationship between EGABA and presynaptic/postsynaptic phase locking.

(A–C) Examples of synaptic delays of increasing magnitude: 0 mS, 1.6 mS, and 8.6 mS, respectively. (D) Histogram of input phase in the postsynaptic neuron as a function of EGABA and varying delay …

Figure 10—figure supplement 4
Relationship between postsynaptic firing properties as a function of EGABA and varying degrees of synchrony between two presynaptic neurons.

(A) Characterization of the varying degrees of presynaptic synchrony defined by the parameter presynaptic offset. The presynaptic offset is the phase difference between the first (red) and second …

Figure 10—figure supplement 5
Relationship between postsynaptic firing properties as a function of EGABA and varying degrees of synchrony between three presynaptic neurons.

(A) Characterization of the varying degrees of presynaptic synchrony defined by the parameter presynaptic offset. The presynaptic offset is the phase difference between the first (red),second …

Figure 10—figure supplement 6
Relationship between postsynaptic firing properties as a function of EGABA and varying degrees of synchrony between four presynaptic neurons.

(A) Characterization of the varying degrees of presynaptic synchrony defined by the parameter presynaptic offset. The presynaptic offset is the phase difference between the first (red),second …

Figure 10—figure supplement 7
Effects of varying EGABA on post synaptic dynamics in the three-neuron motif where neuron 1 projects to neuron 2 and neuron 3 and neuron 2 projects to neuron 3 (motif number 10 from Song et al., 2005).

(A) Phase difference between the two presynaptic neurons (cell 1 and cell 2) as a function of EGABA. (B) Firing rate and coefficient of variation (CV) in the postsynaptic neuron (cell 3) as a function …

Effect of varying EGABA in a network of 100 model SNr neurons with random, sparse connectivity.

(A) Histogram showing the number of neurons receiving zero to eight synaptic inputs. (B) Mean network firing rate as a function of EGABA. (C) Mean network CV as a function of EGABA. Shaded regions in B …

Slow oscillations in the SNr seen under dopamine depleted conditions in vivo are suppressed by channelrhodopsin-2 optogenetic stimulation of GABAergic GPe terminals in the SNr.

(A–B) Example (A) raster plot and (B) power spectrum of a single spiking unit in SNr without (blue) and with (red) optogenetic stimulation of GPe terminals over multiple trials. (C) Frequencies of …

Figure 13 with 2 supplements
Tonic somatic Cl- conductance affects somatic and dendritic EGABA and tunes SNr responses to Str inputs.

(A) Raster plot of spikes in the simulation of an SNr network model containing 50 simulated neurons that receive tonic somatic inhibition from GPe projections. (B) Integrated SNr population activity …

Figure 13—figure supplement 1
Switching from a single dendrite to multiple thin dendrites increases rate but not magnitude of Cl- accumulation and subsequent depolarization of EGABA in response to simulated 40Hz Str stimulation.

Neuronal response (blue) and EGABA dynamics (red) in a neuron with (A,C) two or (B,D) four thin dendrites. For comparison EGABA dynamics in a neuron with a single dendrite is shown in gray in all panels. …

Figure 13—figure supplement 2
Increasing the number of dendrites has no qualitative effect on the the time it takes to generate a pause in SNr activity in response to ramping Str activity.

Relationship between the tonic Cl- conductance and Tpause for (A) one dendrite, (B) two (B1) or four (B2) dendrites with total surface area and capacitance matched to the single dendrite, and (C) two (C1)…

Summary figure/cartoon - GPe output provides tonic Cl load tuning SNr synchrony and the strength of Str inhibition.

Tables

Table 1
Ionic channel parameters.
ChannelParameters
INagNa=35nS/pFENa=50.0mV
m1/2=-30.2mVkm=6.2mV
τm0=0.05msτm1=0.05msτ1/2m=1mV
σm0=1mVσm1=1mV
h1/2=-63.3mVkh=-8.1mV
τh0=0.59msτh1=35.1msτ1/2h=-43.0mV
σh0=10mVσh1=-5mV
s1/2=-30.0mVks=-0.4mV
τs0=10msτs1=50msτ1/2s=-40mV
σs0=18.3mVσs1=-10mVsmin=0.15
INaPgNaP=0.175nS/pF
m1/2=-50.0mVkm=3.0mV
τm0=0.03msτm1=0.146msτ1/2m=-42.6mV
σm0=14.4mVσm1=-14.4mVmmin=0.0
h1/2=-57.0mVkh=-4.0mV
τh0=10.0msτh1=17.0msτ1/2h=-34.0mV
σh0=26.0mVσh1=-31.9mVhmin=0.154
IKgK=50nS/pFEK=-90.0mV
m1/2=-26mVkm=7.8mV
τm0=0.1msτm1=14.0msτ1/2m=-26.0mV
σm0=13.0mVσm1=-12.0mV
h1/2=-20.0mVhm=-10.0mV
τh0=5.0msτh1=20.0msτ1/2h=0.0mV
σh0=10.0mVσh1=-10.0mVhmin=0.6
ICagCa=0.7nS/pFECa=13.27ln(Caout/Cain)
Caout=4.0mMCain, see Equation 18
m1/2=-27.5mVkm=3.0mVτm=0.5ms
h1/2=-52.5mVkh=-5.2mVτh=18.0ms
ISKkSK=0.4mMnSK=4τsk=0.1mS
ILeakgLeak=0.04nS/pFELeak=-60mV
IGABASWGABAGPe=0.2nS/pFEGABAS, see Equation 23τSynE=3.0ms
D0=1.0αD=0.565τD=1000ms
Dmin=0.67WGABASNr=0.1nS/pF
ISD, IDSgC=26.5nS
ITRPC3gTRPC3=0.1nS/pFETRPC3=-37.0mV
IGABADWGABAStr=0.4nS/pFEGABAD, see Equation 23τGABAD=7.2ms
F0=0.145αF=0.125τF=1000ms

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