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Review
. 2006 Apr 15;572(Pt 2):323-34.
doi: 10.1113/jphysiol.2005.100610. Epub 2006 Feb 9.

Tuning and playing a motor rhythm: how metabotropic glutamate receptors orchestrate generation of motor patterns in the mammalian central nervous system

Andrea Nistri  1 , Konstantin Ostroumov, Elina Sharifullina, Giuliano Taccola
Affiliations
Review

Tuning and playing a motor rhythm: how metabotropic glutamate receptors orchestrate generation of motor patterns in the mammalian central nervous system

Andrea Nistri et al. J Physiol. .

Abstract

Repeated motor activities like locomotion, mastication and respiration need rhythmic discharges of functionally connected neurons termed central pattern generators (CPGs) that cyclically activate motoneurons even in the absence of descending commands from higher centres. For motor pattern generation, CPGs require integration of multiple processes including activation of ion channels and transmitter receptors at strategic locations within motor networks. One emerging mechanism is activation of glutamate metabotropic receptors (mGluRs) belonging to group I, while group II and III mGluRs appear to play an inhibitory function on sensory inputs. Group I mGluRs generate neuronal membrane depolarization with input resistance increase and rapid fluctuations in intracellular Ca(2+), leading to enhanced excitability and rhythmicity. While synchronicity is probably due to modulation of inhibitory synaptic transmission, these oscillations occurring in coincidence with strong afferent stimuli or application of excitatory agents can trigger locomotor-like patterns. Hence, mGluR-sensitive spinal oscillators play a role in accessory networks for locomotor CPG activation. In brainstem networks supplying tongue muscle motoneurons, group I receptors facilitate excitatory synaptic inputs and evoke synchronous oscillations which stabilize motoneuron firing at regular, low frequency necessary for rhythmic tongue contractions. In this case, synchronicity depends on the strong electrical coupling amongst motoneurons rather than inhibitory transmission, while cyclic activation of K(ATP) conductances sets its periodicity. Activation of mGluRs is therefore a powerful strategy to trigger and recruit patterned discharges of motoneurons.

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Figures

Figure 1
Figure 1. Topography of mGluRs in the spinal cord and brainstem
Left, top scheme shows that the majority of mGluR immunoreactivity is found on the perisynaptic and extrasynaptic plasma membrane of neurons, and partly on glia. Middle, schematic section of the adult rat spinal cord indicates that mGluR5s are densely expressed in laminae I–III of the dorsal horn (DH) with gradual decrease in deeper laminae. About half of vesicle-containing profiles stained for mGluR5 are also positively stained for GABA (Jia et al. 1999). mGluR1s are mostly distributed throughout laminae III–X (Berthele et al. 1999; Alvarez et al. 2000) with patchy immunoreactivity of varying intensity in somata and dendrites of spinal motor nuclei (MN) including motoneurons and interneurons (see inset marked by open arrow) of the ventral horn (VH), and in presynaptic axon terminals (Alvarez et al. 1997, 2000). Group II and III are scattered throughout the spinal cord with predominance in the DH (Berthele et al. 1999) and even some glial labelling (Ohishi et al. 1995; Jia et al. 1999; Azkue et al. 2000, 2001). In addition, group II mGluR3 mRNA is expressed in the small cells surrounding motoneurons, while group III mGluR4 mRNA is present in the spinal motoneurons (Berthele et al. 1999). Right, in the medulla oblongata group I (mGluR1a/5), group II (mGluR2/3) and group III (mGluR7/8) mGluRs (Hay et al. 1999; Pamidimukkala et al. 2002) show different distribution throughout subnuclei of NTS and of the ventrolateral medulla. Only mGluR1 and mGluR8 subtypes are expressed by hypoglossal motoneurons (XII; Hay et al. 1999; Pamidimukkala et al. 2002).
Figure 2
Figure 2. Cellular actions of group I mGluR activation
Left (top), schematic diagram showing the electrophysiological arrangements used for the rat isolated spinal cord preparation with sharp electrode intracellular recording (I; green) from lumbar motoneurons, DR electrical stimulation (step symbol; red) and ventral root (VR) antidromic stimuli to elicit recurrent IPSP (rI; red). A, application of DHPG induces membrane depolarization (with associated input resistance rise), membrane oscillations and enhancement in synaptic activity (large deflections are truncated spikes). B shows faster time base record of motoneuron oscillations with spikes taken from the trace marked by filled bar (voltage calibration in B applies also to A). Data are reproduced with permission from Marchetti et al. (2003, . Right (top), schematic coronal section of the brainstem to show location of patch clamp electrode (under voltage clamp, VC, blue; current clamp, CC, green) for recording from HMs. The stimulating electrode is placed in the DMRC as shown (step symbol, red). C, under VC conditions application of DHPG induces inward current with emergence of fast oscillations and subsequent bursts; 10 min washout restores control conditions. Faster time base record taken from the trace depicts fast oscillations subsequently followed by bursts. D, paired recording from adjacent HMs shows strong phase coincidence of DHPG-evoked oscillatory patterns under voltage (top) and current (bottom) clamp. Data are reproduced, with permission, from Sharifullina et al. (2004, 2005).
Figure 3
Figure 3. Network actions of group I mGluR activation
A, disinhibited bursting evoked by block of synaptic inhibition (red trace; 1 μ m strychnine plus 20 μ m bicuculline application) is accelerated by DHPG (5 μ m; crimson trace) which significantly reduces burst duration and periodicity. Because disinhibited bursting is believed to originate from the rhythmic discharges by CPG, this effect suggests activation of CPG interneurons by DHPG. eV (green), extracellular DC recording from VR. B, fictive locomotor patterns induced by co-application of NMDA and 5-HT is depressed by 20 μ m DHPG and restored by increasing the NMDA concentration to 9 μ m. C, conversely, fictive locomotor patterns brought below threshold by decreasing the 5-HT concentration are restored by adding a small (5 μ m) dose of DHPG. Data are reproduced, with permission, from Taccola et al. (2004b). D, fast inward current recorded (under voltage clamp, V) from single HM induced by puffer application (P) of AMPA is followed by rhythmic oscillations when occurring in coincidence with a concentration of DHPG (5 μ m) subthreshold for oscillations. E, electrically evoked EPSP (by stimulating the DMRC, see step symbol in red) recorded under current clamp (C, green) in control solution (red trace) generates spike and oscillations (crimson trace; see also inset at faster time scale for record corresponding to the open bar) when repeated in the presence of DHPG (5 μ m). F, comparison of two HMs (left and right) at similar membrane potential in the presence of DHPG (20 μ m). The one on the left (red) produces high-frequency firing without oscillations, while the one on the right (crimson) generates oscillations with lower firing rate. Data reproduced with permission from Sharifullina et al. (2005).
Figure 4
Figure 4. Idealized diagram of motor networks activated by group I mGluRs
Different types of neuron are indicated by dissimilar cell body shapes: their inputs are compacted into a single dendritic shaft, while their output is indicated by a horseshoe symbol colour-coded according to the released transmitter. Group I mGluRs (mainly found at extrasynaptic sites) are assigned on the basis of cell type rather than specific cell compartments. Left, schematic representation of spinal networks (one side only of the segmental circuit is shown) with excitatory (glutamatergic, red; cholinergic, grey), inhibitory (GABAergic, light blue; glycinergic, dark blue) and electrical (yellow) synapses. CPG interneurons are collectively lumped into a black box with inputs from DRs, and output to premotoneurons and motoneurons. mGluR1 and mGluR5 receptors (red pentagons) are expressed by various cell types. While mGluR5 activity is believed to generate motoneuron oscillations, mGluR1 activity is thought responsible for network depolarization (including CPG elements and motoneurons). Gap junctions and depression of Renshaw cell activity probably concur to produce oscillation synchronicity. Note that facilitation of glycinergic interneuron (blue circle)-bearing mGluR1 receptors contributes to restrain network excitation. Right, network of HMs bearing mGluR1 receptors and coupled via gap junctions. HM expression of KATP channels enables pacing of bursting at low frequency. Network synaptic inputs important for oscillatory activity are also shown. Note apparent lack of mGluR5 receptors.
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