Physiological Function of Persistent Inward Currents in Motor Neurons

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ABSTRACT Motor neurons receive synaptic inputs from many other neurons and convert these inputs into frequency-coded messages that are relayed to muscle fibers to cause contraction. It is often assumed that motor neurons generate spikes at rates in proportion to the excitatory synaptic input received. It is now recognized, however, that motor neurons have active processes, such as persistent inward currents (PICs), that may markedly alter the relationship between synaptic input and firing rate output. PICs represent a neuromodulator-mediated intrinsic source of membrane depolarization that can even lead to self-sustained firing of motor neurons, i.e., prolonged spiking in the absence of synaptic input. Several ideas have been forwarded as to the functional significance of PICs, both in terms of the control of normal motor function and as an impaired process contributing to various neurological disorders. Indeed, some investigators have suggested that PICs provide the primary source of depolarizing current to motor neurons during all forms of activity, whereas others speculate that PICs are only active during periods of high stress and arousal. Yet the extent to which PICs contribute to natural motor neuron activity is not known. Therefore, the goal of this project is to directly ascertain the role that PICs play during voluntary muscle contraction using an animal model wherein the ion channels (L-type calcium), thought to be primary mediators of motor neuron PICs, are selectively disabled (Aim 1) or enabled (Aim 2). We will do this by recording motor unit activity in plantar flexor muscles of rats voluntarily exerting target isometric forces in the presence and absence of intrathecally injected nimodipine, an L-type Ca+2 channel blocker (Aim 1), and serotonin, a known promotor of PICs (Aim 2). Changes in motor unit firing rate (and recruitment) recorded under drug conditions will be compared to the same units recorded prior to drug delivery while the animal holds the same force. These comparisons will provide direct knowledge of the role PICs play in shaping natural motor unit activity – a topic of debate since the discovery of PICs in the late 1970s. Furthermore, this study will add to our understanding of PIC dysfunction, implicated in neurological disorders such as spasticity and amyotrophic lateral sclerosis.