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1.  Staircase Currents in Motoneurons: Insight into the Spatial Arrangement of Calcium Channels in the Dendritic Tree 
In spinal motoneurons, activation of dendritically located depolarizing conductances can lead to amplification of synaptic inputs and the production of plateau potentials. Immunohistochemical and computational studies have implicated dendritic CaV1.3 channels in this amplification and suggest that CaV1.3 channels in spinal motoneurons may be organized in clusters in the dendritic tree. Our goal was to provide physiological evidence for the presence of multiple discrete clusters of voltage-gated calcium channels in spinal motoneurons and to explore the spatial arrangement of these clusters in the dendritic tree. We recorded voltage-gated calcium currents from spinal motoneurons in slices of mature mouse spinal cords. We demonstrate that single somatic voltage-clamp steps can elicit multiple inward currents with varying delays to onset, resulting in a current with a “staircase”-like appearance. Recordings from cultured dorsal root ganglion cells at different stages of neurite development provide evidence that these currents arise from the unclamped portions of the dendritic tree. Finally, both voltage- and current-clamp data were used to constrain computer models of a motoneuron. The resultant simulations impose two conditions on the spatial distribution of CaV channels in motoneuron dendrites: one of asymmetry relative to the soma and another of spatial separation between clusters of CaV channels. We propose that this compartmentalization would provide motoneurons with the ability to process multiple sources of input in parallel and integrate this processed information to produce appropriate trains of action potentials for the intended motor behavior.
PMCID: PMC5065350  PMID: 19386931 CAMSID: cams1856
2.  Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior 
Neuron  2013;78(1):191-204.
Accurate motor performance depends on the integration in spinal microcircuits of sensory feedback information. Hand grasp is a skilled motor behavior known to require cutaneous sensory feedback, but spinal microcircuits that process and relay this feedback to the motor system have not been defined. We sought to define classes of spinal interneurons involved in the cutaneous control of hand grasp in mice, and show that dI3 interneurons, a class of dorsal spinal interneurons marked by expression of Isl1, convey input from low threshold cutaneous afferents to motoneurons. Mice in which the output of dI3 interneurons has been inactivated exhibit deficits in motor tasks that rely on cutaneous afferent input. Most strikingly, the ability to maintain grip strength in response to increasing load is lost following genetic silencing of dI3 interneuron output. Thus, spinal microcircuits that integrate cutaneous feedback crucial for paw grip rely on the intermediary role of dI3 interneurons.
PMCID: PMC4535710  PMID: 23583114
3.  Spinal interneurons providing input to the final common path during locomotion 
Progress in brain research  2010;187:81-95.
As the nexus between the nervous system and the skeletomuscular system, motoneurons effect all behaviour. As such, motoneuron activity must be well-regulated so as to generate appropriately timed and graded muscular contractions. Accordingly, motoneurons receive a large number of both excitatory and inhibitory synaptic inputs from various peripheral and central sources. Many of these synaptic contacts arise from spinal interneurons, some of which belong to spinal networks responsible for the generation of locomotor activity. Although the complete definition of these networks remains elusive, it is known that the neural machinery necessary to generate the basic rhythm and pattern of locomotion is contained within the spinal cord. One approach to gaining insights into spinal locomotor networks is to describe those spinal interneurons that directly control the activity of motoneurons, so called “last-order” interneurons. In this review, we briefly survey the different populations of last-order interneurons that have been identified using anatomical, physiological, and genetic methodologies. We discuss the possible roles of these identified last-order interneurons in generating locomotor activity, and in the process, identify particular criteria that may be useful in identifying putative last-order interneurons belonging to spinal locomotor networks.
PMCID: PMC3150186  PMID: 21111202 CAMSID: cams1859
4.  Estimates of the Location of L-type Ca2+ Channels in Motoneurons of Different Sizes: A Computational Study 
Journal of neurophysiology  2007;97(6):4023-4035.
In the presence of monoamines, L-type Ca2+ channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca2+ channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca2+ channels and test the hypothesis that the location of L-type Ca2+ channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca2+ channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca2+ channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.
PMCID: PMC2930907  PMID: 17428909 CAMSID: cams1475
5.  Relative Location of Inhibitory Synapses and Persistent Inward Currents Determines the Magnitude and Mode of Synaptic Amplification in Motoneurons 
Journal of neurophysiology  2007;99(2):583-594.
In some motoneurons, L-type Ca2+ channels that partly mediate persistent inward currents (PICs) have been estimated to be arranged in 50- to 200-μm-long discrete regions in the dendrites, centered 100 to 400 μm from the soma. As a consequence of this nonuniform distribution, the interaction between synaptic inputs to motoneurons and these channels may vary according to the distribution of the synapses. For instance, >93% of synapses from Renshaw cells have been observed to be located 65 to 470 μm away from the cell body of motoneurons. Our goal was to assess whether Renshaw cell synapses are distributed in a position to more effectively control the activation of the L-type Ca2+ channels. Using compartmental models of motoneurons with L-type Ca2+ channels distributed in 100-μm-long hot spots centered 100 to 400 μm away from the soma, we compared the inhibition generated by four distributions of inhibitory synapses: proximal, distal, uniform, and one based on the location of Renshaw cell synapses on motoneurons. Regardless of whether the synapses were activated tonically or transiently, in the presence of L-type Ca2+ channels, inhibitory synapses distributed according to the Renshaw cell synapse distribution generate the largest inhibitory currents. The effectiveness of a particular distribution of inhibitory synapses in the presence of PICs depends on their ability to deactivate the channels underlying PICs, which is influenced not only by the superposition between synapses and channels, but also by the distance away from the somatic voltage clamp.
PMCID: PMC2930908  PMID: 18046006 CAMSID: cams1477
6.  Multiple Modes of Amplification of Synaptic Inhibition to Motoneurons by Persistent Inward Currents 
Journal of neurophysiology  2007;99(2):571-582.
The ability of inhibitory synaptic inputs to dampen the excitability of motoneurons is augmented when persistent inward currents (PICs) are activated. This amplification could be due to an increase in the driving potential of inhibitory synapses or the deactivation of the channels underlying PICs. Our goal was to determine which mechanism leads to the amplification of inhibitory inputs by PICs. To reach this goal, we measured inhibitory postsynaptic currents (IPSCs) in decerebrate cats during somatic voltage-clamp steps. These IPSCs were generated by tonic activation of Renshaw cells. The IPSCs exhibited a rapid rise and a slower decay to a plateau level. Activation of PICs always led to an increase in the peak of the IPSC, but the amount of decay after the peak of the IPSC was inversely related to the size of the IPSC. These results were replicated in simulations based on compartmental models of motoneurons incorporating distributions of Renshaw cell synapses based on anatomical observations, and L-type calcium channels distributed as 100-μm-long hot spots centered 100 to 400 μm away from the soma. For smaller IPSCs, amplification by PICs was due to an increase in the driving force of the inhibitory synaptic current. For larger IPSCs, amplification was caused by deactivation of the channels underlying PICs leading to a lesser decay of the IPSCs. As a result of this change in the time course of the IPSC, deactivation of the channels underlying PICs leads to a greater amplification of the total inhibitory synaptic current.
PMCID: PMC2930909  PMID: 18046007 CAMSID: cams1478

Results 1-6 (6)