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