How membrane currents interact
to shape the integrative properties of
motoneurones
Claude Meunier
The final common pathway
Descending pathways
Neuromodulation
Spinal inputs
MN
Excitation
Ia
Ib
Spindle
Tendon organ
Slow and Fast-type motoneurones
Jami et al., 1982
Inhibition
Role of subthreshold currents in
synaptic integration and firing
Deeply anaesthetised cats
Intracellular recordings
Currents added by dynamic clamp
Experiments combined with simple models
A physiological role for Ih
Little Ih in Slow-type motoneurones
F-type motoneurones display a subthreshold resonance
Manuel et al., 2007
fR = 11 ± 3 Hz
Resonance is caused by Ih
Manuel et al., 2007
Suppressed by depolarisation and enhanced by hyperpolarisation
Blocked by ZD-7288
which is located in dendrites
Rall’s model with Ih
More than 90% of Ih in dendrites
(to be confirmed)
Manuel et al., 2007
PICs enhance or suppress the resonance
Na+ PIC
PICs are depressed
by barbiturates
Harv ey et al., 2005
Experiments
Ca2+ PIC
Model
Manuel et al., 2007
Recruitment of motoneurones by
proprioceptive input
Resonant (F-type)
Recovering balance
Manuel et al., 2007
Non-resonant (S-type)
Maintaining posture
The AHP enters the picture
The AHP current regulates the discharge
Anaesthetised cats
Manuel et al., 2006
A solvable model
Integrate-and-fire model with AHP conductance
Effective voltage dependence
z = zafter e- t/x
AHP
zafter = a + (1 - a) z before
- t/x
z 6t @ = 1 - (1ae
- a) e- 1/fx
AHP
AHP
Meunier & Borejsza, 2005
Two time-scales analysis
Meunier & Borejsza, 2005
First interval:
The gain is in inverse proportion to the charge transfered by the AHP current
Doubling the input conductance decreases the gain by less than 10%.
Experimental validation
Shunting inhibition (Dynamic clamp)
Gsyn = 0.25 µS
Gsyn = 0.5 µS
Brizzi et al., 2004
Z(t) is the phase response
TAHP
Manuel et al., 2006
!
Uncontaminated by Ih
Manuel et al., 2005
GAHP and VK
5 to 10% accuracy
AHP controls firing variability
Manuel et al., 2006
Neuromodulation may induce bistability
Persistent calcium current
Hultborn et al., 2004
Ballou et al., 2006
Hounsgaard et al., 1988
The BRK model
Weak coupling : gc = 0.1 mS/cm2
Studies with this model have supported the
hypothesis that the bistable firing patterns
require a nonuniform distribution of ionic
conductances
and,
specifically,
a
segregation
of
plateau-generating
currents from spike-generating currents.
Booth, Rinzel & Kiehn, 1997
Bistability of dendritic I-V curve
Is it relevant for motoneurones?
Parameters
Motoneurone
BRK model
ρ
10
2.7
τm
6 ms
2 ms
τAHP
15 ms
50 ms
GAHP/Gin
0.3
0.02
(no neurodulation)
Weak coupling -> Dendritic voltage is attenuated and low-pass filtered
Stationary voltage : 70%
Spikes : 96%
Distal location of PIC: 1.2 λ (L = 1-1.5)
Ballou et al., 2006
An alternative model
More realistic parameters:
ρ, Gin, GAHP , τm, τAHP, PIC location
X 10
X
Bistability stems from the competition
between the dendritic PIC and the
somatic AHP current
70
0
60
1
-10
0.8
V (mV)
40
30
0.6
-30
D
f (Hz)
-20
0.4
-40
20
0
-30
0.2
-50
10
-60
-20
-10
0
10
20
2
I ( µA/cm )
30
40
50
0
4
4.02
4.04
4.06
t (s)
4.08
4.1
PIC activation
50
Somatic bistability: Model
Calcium PIC at the soma only
X
Ica
-L
Calcium decoupling between PIC
and AHP current is required
Li and Bennett 2007
and experiments
Frequency (Hz)
Counterclockwise hysteresis
Firing bistability
Control
PIC
Conclusions
Subthreshold currents shape the integrative properties of motoneurones
A major role is played by the competition between stabilizing and destabilizing
currents:
Ih and PICs below threshold
-> selective amplification of synaptic input and recruitment of motoneurones
AHP current and Calcium PIC above threshold
-> control of the firing states
Neuromodulation controls the balance between these currents according to the
physiological requirements
Thanks to
Daniel Zytnicki
Karol Borejsza
Laurent Brizzi
Marin Manuel
Maud Donnet
Audrey Goulian
and to all of you for your attention