Persistent inward currents in spinal motoneurons and their influence on human motoneuron firing patterns

Abstract

Persistent inward currents (PICs) are present in many types of neurons and likely have diverse functions. In spinal motoneurons, PICs are especially strong, primarily located in dendritic regions, and subject to particularly strong neuromodulation by the monoamines serotonin and norepinephrine. Because motoneurons drive muscle fibers, it has been possible to study the functional role of their PICs in motor output and to identify PIC-mediated effects on motoneuron firing patterns in human subjects. The PIC markedly amplifies synaptic input, up to fivefold or more, depending on the level of monoaminergic input. PICs also tend to greatly prolong input time course, allowing brief inputs to initiate long-lasting self-sustained firing (i.e., bistable behavior). PIC deactivation usually requires inhibitory input and PIC amplitude can increase to repeated activation. All of these behaviors markedly increase motoneuron excitability. Thus, in the absence of monoaminergic input, motoneuron excitability is very low. Yet PICs have another effect: once active, they tend to sharply limit efficacy of additional synaptic input. All of these PIC effects have been detected in motoneuron firing patterns in human subjects and, hence, PICs are likely a fundamental component of normal motor output.

Fig. 1

Motoneuron frequency-current functions in the absence of neuromodulatory input. Each function has a sharp threshold current (x axis) followed an approximately linear increase in firing rate. At high input-output levels there is a transition to a steeper, secondary range. Motoneuron-innervated slow (S) twitch muscle fibers have the lowest threshold currents, as shown by the example at the left. Those innervating fast, fatigue-resistant (FR) fibers have moderate thresholds and those innervating fast, fatiguable (FF) fibers the highest thresholds. Thus the motoneuron tends to be recruited in order of S, FR, and then FF. Data are based on realistic computer simulations of motoneuron properties (Heckman and Binder 1991).

Fig. 2

Motoneuron current-voltage (I–V) functions in the presence of strong neuromodulatory input. (A) A slow linear increase and then decrease in voltage command (black triangular shaped trace) evokes a complex current response. The persistent inward current (PIC) is manifest as large downward deflections on both the rising (initial peak) and falling (sustained peak) phases. (B) I–V plot for the data in A. The amplitude of the PIC is calculated in comparison with the linear leak I–V function (dashed line). Data are from Lee and Heckman (1998a).

Fig. 3

Amplification and prolongation of synaptic input by the dendritic persistent inward current (PIC) in a low-threshold, type S motoneuron. (A) Steady synaptic input was generated by 1.5 seconds of high-frequency activation of a monosynaptic, ionotropic source, muscle spindle Ia afferents. At a hyperpolarized holding potential (−90 mV; green trace), this input produced a steady current with a sharp onset and offset. At depolarized holding potential (~−55 mV; red trace), the very same input is greatly amplified and prolonged by the PIC. Baseline holding currents are removed to allow the traces to be superimposed. (B) The difference between the currents in A reflects the net contribution of the dendritic PIC. (C) In unclamped conditions, the same input produces a steady excitatory postsynaptic potential (EPSP) at hyperpolarized levels (~−90 mV). At a more depolarized level (−70 mV), the same input evokes intense repetitive firing, following by continued, self-sustained firing at a lower level when the input is removed. Data are from Lee and Heckman (1996).

Fig. 4

Serotonin contacts on a spinal motoneuron. Each dot represents a synaptic bouton containing serotonin. Note the coverage includes distal dendrites. This figure was reproduced from Figure 4 of Alvarez and others (1998). Distribution of 5-hydroxytryptamine-immunoreactive boutons on alpha-motoneurons in the lumbar spinal cord of adult cats. J Comp Neurol 393:69–83. Copyright Wiley-Liss Inc. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

Fig. 5

Dependence of persistent inward current (PIC) amplification on level of neuromodulatory input. Each trace shows the synaptic current generated at the soma by a steady synaptic input while the voltage clamp holding potential is linearly depolarized. (Red trace) Low levels of drive (acutely spinalized preparation to eliminate descending monoaminergic input). (Blue trace) Medium level (intact cord decerebrate preparation, with tonic descending monoaminergic drive). (Green trace) High level (intact cord decerebrate with exongenous administration of the noradrenergic agonist α1-agonist methoxamine). The stronger the neuromodulatory drive, the larger the PIC-mediated amplification. But once the PIC is activated (above −40 mV), synaptic current decreases dramatically. Data are from Lee and Heckman (2000).

Fig. 6

Effect of descending monoaminergic input on the net input-output gain of a motor pool and the muscle it innervates. Computer simulations closely based on the properties of the motor units of the cat medial gastrocnemius muscle and motor pool. As monoaminergic input increases, overall slope (gain) greatly increases. Dashed line and arrow: approximate maximum ionotropic input that descending and sensory systems can generate in motoneurons. Dotted line and arrow: force and input range required for posture in this muscle.

Fig. 7

Firing patterns in response to synaptic input in cat and man. (A) Firing response to linearly increasing injected current in cat motoneuron with a strong persistent inward current (PIC). (B) Synaptic currents in the same motoneuron generated by linear muscle stretch. The lower, thin trace was generated when the cell was held hyperpolarized to avoid activation of the dendritic PIC. The thick trace was the response to the same stretch, but with the clamp holding potential placed at the voltage at which spiking would occur in the unclamped state. The extra current and the saturation reflect PIC activation. (C) Firing pattern to the same stretch, same cell. (D) Example of motor unit firing in a human subject during a voluntary contraction in which joint torque increases linearly. Biceps muscle. Data are from Mottram C (unpublished studies).

Fig. 8

A very short input can activate a persistent inward current (PIC) that continues after the input ends. Input generated by a short-lasting (100 ms) excitatory input mediated by high-frequency activation of muscle spindle Ia afferents. (Green trace) Current generated at a hyperpolarized holding potential, avoiding PIC activation. (Red trace) Depolarized holding potential, allowing PIC activation. Data from Heckman CJ (unpublished studies).

Fig. 9

Two distinct modes of behavior in a single motoneuron. Spikes have been blocked (QX314 in the intracellular electrode). On the left, a scratch reflex has been evoked by irritating the ipsilateral ear. Note the onset of inhibition (arrow) before the scratch oscillations. On the right, irritation of the contralateral ear produced a completely different response in the same neuron, a weight support response mediated by a sustained plateau potential with no inhibition. Input conductance of the cell during the scratch was substantially larger than during the weight support responses. Data from Perreault (2002), used with permission of the author.