Investigating the effects of propofol-induced tonic inhibition on rhythmic neural activity in a hippocampal interneuron network

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Investigating the effects of propofol-induced tonic inhibition on rhythmic neural activity in a hippocampal

interneuron network

Francesco Giovannini, Jean-Baptiste Schneider, Laure Buhry

To cite this version:

Francesco Giovannini, Jean-Baptiste Schneider, Laure Buhry. Investigating the effects of propofol- induced tonic inhibition on rhythmic neural activity in a hippocampal interneuron network. Eleventh Bernstein Conference 2015, Sep 2015, Heidelberg, Germany. Proceedings of the Eleventh Bernstein Conference 2015, 2015. �hal-01191426�

(2)

Investigating the effects of propofol-induced tonic

inhibition on rhythmic neural activity in a hippocampal interneuron network

Francesco Giovannini ^1* , Jean-Baptiste Schneider ¹ , Laure Buhry ¹

1 Neurosys Team, INRIA, LORIA, Université de Lorraine, CNRS, Nancy, France

* [email protected]

Motivation

• Propofol-induced sedation is achieved by positively modulating GABAergic inhibitory activity [1]

• Synaptic and extrasynaptic GABA _A receptors are ubiquitous in the brain [2]

• GABAergic hippocampal interneurons have been shown capable of generating and maintaining γ -band (20 − 80) Hz rhythmic neural activity [3]

• γ -band oscillations are thought to underlie long-term memory consolidation [4]

• We study the effect of the propofol-induced extrasynaptic GABAergic modulation [5] on such self-emerging synchronous activity

Neuron Model

• Neuron Model:

C _m · dV

dt = −I _L − I _K − I _{N a} − I _Syn − I _{SynT onic} + I _Stim

• Hodgkin-Huxley Currents and Stimulation:

I _Leak = f (V _m ) I _K = f (V _m , n ⁴ ) I _{N a} = f (V _m , m ³ , h) I _Stim = 0.4 nA

Synapses and Propofol

Schematic of GABA (orange) binding on synaptic and extrasynaptic receptors causing Cl

⁻

ion influx in the postsynaptic neuron. Extrasynaptic GABA receptors mediate tonic inhibition, and are potentiated by extracellular propofol (red). Propofol also binds on synaptic GABA receptors (not modelled in the present work, thus not shown).

• Inhibitory Postsynaptic (Phasic) Current:

I _Syn = −g _i · (V _m − E _i ) dg _i

dt = − g _i

τ _i g _i ← g _i + w _ii

• Inhibitory Extrasynaptic (Tonic) Current [5]:

I _{SynT onic} = −g _t · (V _m − E _i ) g _t ∝ [C ₁₂ H ₁₈ O] _o (propofol)

• Network Topology:

N = 100 (neurons) ρ = 0.6 (connection probability)

• Network Synchronisation Measure [3]:

κ _i,j (τ ) =

P L

l=1 X _i (l)Y _j (l) q

P L

l=1 X _i (l) ^P ^L _l=1 Y _j (l)

κ(τ ) =

P N i=1

P N

j =1 κ _i,j (τ )

N ² 0 ≤ κ(τ ) ≤ 1

X _i (l), Y _j (l) ∈ {0, 1} l = 0, 1, 2, ..., L L = t _sim

τ τ = 10 ms

Results – γ -band Synchronisation

0 100 200 300 400 500 600 700 800 900 1000

0 20 40 60 80 100

Population activity for g

t = 0 nS

Time (ms)

Neurons

0 100 200 300 400 500 600 700 800 900 1000

0 10 20 30

Population Firing Rate

Time (ms)

Frequency (Hz)

Networks of Hippocampal interneurons display synchronous activity with a value of κ(τ ) = 0.4, in the γ -band at an oscillatory frequency of f

_osc

' 25 Hz , when subject to a constant stimulation, in the absence of propofol.

Results – Increasing Anaesthetic Dosage

0 100 200 300 400 500 600 700 800 900 1000

0 20 40 60 80 100

t = 18 nS

Time (ms)

Neurons

0 100 200 300 400 500 600 700 800 900 1000

0 20 40

Time (ms)

Frequency (Hz)

Increasing the dosage of propofol to g

_t

= 18 nS causes stronger synchrony amongst the neurons in the network κ(τ ) = 0.8, while slowing down the oscillatory activity to a frequency of f

_osc

' 15 Hz.

0 100 200 300 400 500 600 700 800 900 1000

0 20 40 60 80 100

t = 21 nS

Time (ms)

Neurons

0 100 200 300 400 500 600 700 800 900 1000

0 10 20

Time (ms)

Frequency (Hz)

Increasing the dosage of propofol to g

_t

≥ 21 nS weakens the synchrony amongst the neurons in the network κ(τ ) = 0.2, and slows down the oscillatory activity to a frequency of f

_osc

' 10 Hz .

Results – Propofol Synchrony and Oscillations

0 2 4 6 8 10 12 14 16 18 20 22

0 0.2 0.4 0.6 0.8 1

Mean Population Synchrony - κ(τ)

Coherence - K

Tonic (Extrasynaptic) Conductance (nS)

0 2 4 6 8 10 12 14 16 18 20 22

0 5 10 15 20

Mean Population Firing Rate

Firing Rate (Hz)

0 2 4 6 8 10 12 14 16 18 20 22

0 10 20 30 40 50

Mean Population Oscillation Frequency

Oscillations (Hz)

Increasing the propofol dosage – by acting on the tonic conductance g

_t

– causes the overall activity of the network to decrease, until a critical value of g

_t

= 14 nS at which both the network synchronisation and firing rate increase. When

the concentration value reaches a value of g

_t

≥ 21 nS the activity, synchronous or otherwise, fades out.

Conclusion

• Anaesthetics target both synaptic and extrasynaptic GABA _A receptors

• Increasing the dosage of anaesthetic agents can strengthen synchronous activity in networks of hippocampal neurons

• Paradoxical excitation behaviours might be mediated by the effects of anaesthetics on extrasynaptic GABA _A receptors

References

[1] C. Vanlersberghe and F. Camu, “Propofol,” in Modern Anesthetics: Handbook of Experimental Pharmacology (J. Schüttler and H. Schwilden, eds.), no. 182, pp. 227–252, Springer Verlag, 2008.

[2] D. Belelli, N. L. Harrison, J. Maguire, R. L. Macdonald, M. C. Walker, and D. W. Cope, “Extrasynaptic GABAA receptors: form, pharmacology, and function.,”

The Journal of Neuroscience : the official journal of the Society for Neuroscience, vol. 29, pp. 12757–63, Oct. 2009.

[3] X.-J. Wang and G. Buzsáki, “Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.,” The Journal of Neuroscience : the official journal of the Society for Neuroscience, vol. 16, pp. 6402–13, Oct. 1996.

[4] N. Axmacher, F. Mormann, G. Fernández, C. E. Elger, and J. Fell, “Memory formation by neuronal synchronization.,” Brain research reviews, vol. 52, pp. 170–82, Aug. 2006.

[5] A. Hutt and L. Buhry, “Study of GABAergic extra-synaptic tonic inhibition in single neurons and neural populations by traversing neural scales: application to propofol-induced anaesthesia.,” Journal of computational neuroscience, vol. 37, pp. 417–37, Dec. 2014.

Investigating the effects of propofol-induced tonic inhibition on rhythmic neural activity in a hippocampal interneuron network

Investigating the effects of propofol-induced tonic inhibition on rhythmic neural activity in a hippocampal

interneuron network

Investigating the effects of propofol-induced tonic

inhibition on rhythmic neural activity in a hippocampal interneuron network

Francesco Giovannini 1* , Jean-Baptiste Schneider 1 , Laure Buhry 1

1 Neurosys Team, INRIA, LORIA, Université de Lorraine, CNRS, Nancy, France

* [email protected]

Motivation

• Propofol-induced sedation is achieved by positively modulating GABAergic inhibitory activity [1]

• Synaptic and extrasynaptic GABA A receptors are ubiquitous in the brain [2]

• GABAergic hippocampal interneurons have been shown capable of generating and maintaining γ -band (20 − 80) Hz rhythmic neural activity [3]

• γ -band oscillations are thought to underlie long-term memory consolidation [4]

• We study the effect of the propofol-induced extrasynaptic GABAergic modulation [5] on such self-emerging synchronous activity

Neuron Model

• Neuron Model:

C m · dV

dt = −I L − I K − I N a − I Syn − I SynT onic + I Stim

• Hodgkin-Huxley Currents and Stimulation:

I Leak = f (V m ) I K = f (V m , n 4 ) I N a = f (V m , m 3 , h) I Stim = 0.4 nA

Synapses and Propofol

Schematic of GABA (orange) binding on synaptic and extrasynaptic receptors causing Cl

ion influx in the postsynaptic neuron. Extrasynaptic GABA receptors mediate tonic inhibition, and are potentiated by extracellular propofol (red). Propofol also binds on synaptic GABA receptors (not modelled in the present work, thus not shown).

• Inhibitory Postsynaptic (Phasic) Current:

I Syn = −g i · (V m − E i ) dg i

dt = − g i

τ i g i ← g i + w ii

• Inhibitory Extrasynaptic (Tonic) Current [5]:

I SynT onic = −g t · (V m − E i ) g t ∝ [C 12 H 18 O] o (propofol)

• Network Topology:

N = 100 (neurons) ρ = 0.6 (connection probability)

• Network Synchronisation Measure [3]:

κ i,j (τ ) =

P L

l=1 X i (l)Y j (l) q

P L

l=1 X i (l) P L l=1 Y j (l)

κ(τ ) =

P N i=1

P N

j =1 κ i,j (τ )

N 2 0 ≤ κ(τ ) ≤ 1

X i (l), Y j (l) ∈ {0, 1} l = 0, 1, 2, ..., L L = t sim

τ τ = 10 ms

Results – γ -band Synchronisation

Networks of Hippocampal interneurons display synchronous activity with a value of κ(τ ) = 0.4, in the γ -band at an oscillatory frequency of f

' 25 Hz , when subject to a constant stimulation, in the absence of propofol.

Results – Increasing Anaesthetic Dosage

Increasing the dosage of propofol to g

= 18 nS causes stronger synchrony amongst the neurons in the network κ(τ ) = 0.8, while slowing down the oscillatory activity to a frequency of f

' 15 Hz.

Increasing the dosage of propofol to g

≥ 21 nS weakens the synchrony amongst the neurons in the network κ(τ ) = 0.2, and slows down the oscillatory activity to a frequency of f

' 10 Hz .

Results – Propofol Synchrony and Oscillations

Increasing the propofol dosage – by acting on the tonic conductance g

– causes the overall activity of the network to decrease, until a critical value of g

= 14 nS at which both the network synchronisation and firing rate increase. When

the concentration value reaches a value of g

≥ 21 nS the activity, synchronous or otherwise, fades out.

Conclusion

• Anaesthetics target both synaptic and extrasynaptic GABA A receptors

• Increasing the dosage of anaesthetic agents can strengthen synchronous activity in networks of hippocampal neurons

• Paradoxical excitation behaviours might be mediated by the effects of anaesthetics on extrasynaptic GABA A receptors

References

Francesco Giovannini ^1* , Jean-Baptiste Schneider ¹ , Laure Buhry ¹

• Synaptic and extrasynaptic GABA _A receptors are ubiquitous in the brain [2]

C _m · dV

dt = −I _L − I _K − I _{N a} − I _Syn − I _{SynT onic} + I _Stim

I _Leak = f (V _m ) I _K = f (V _m , n ⁴ ) I _{N a} = f (V _m , m ³ , h) I _Stim = 0.4 nA

I _Syn = −g _i · (V _m − E _i ) dg _i

dt = − g _i

τ _i g _i ← g _i + w _ii

I _{SynT onic} = −g _t · (V _m − E _i ) g _t ∝ [C ₁₂ H ₁₈ O] _o (propofol)

κ _i,j (τ ) =

l=1 X _i (l)Y _j (l) q

l=1 X _i (l) ^P ^L _l=1 Y _j (l)

j =1 κ _i,j (τ )

N ² 0 ≤ κ(τ ) ≤ 1

X _i (l), Y _j (l) ∈ {0, 1} l = 0, 1, 2, ..., L L = t _sim

• Anaesthetics target both synaptic and extrasynaptic GABA _A receptors

• Paradoxical excitation behaviours might be mediated by the effects of anaesthetics on extrasynaptic GABA _A receptors