On the role of metabotropic glutamate receptors in motor control : analysis of synaptic, cellular and network properties

The organization of neurons into neuronal networks is a basic feature of the central nervous system. An understanding of the function of neuronal networks requires knowledge on both synaptic connectivity and cellular properties. In the lamprey the neuronal network generating the alternating muscle activity during swimming consists of excitatory glutamatergic and inhibitory glycinergic neurons. The activity of the spinal locomotor network is subject to influence from various modulators acting on specific receptors, including metabotropic glutamate receptors (mGluRs). The aim of this work was to analyze the mechanisms of modulation of cellular and synaptic properties by group I, II and III mGluRs and thereby their role in regulating the activity of the locomotor network in lamprey.

Two different mGluRs, belonging to group II and III, inhibit synaptic transmission from reticulospinal axons to spinal neurons. These mGluRs also inhibit intraspinal and sensory synaptic transmission. This inhibition occurs without any change in the membrane potential, input resistance or receptor sensitivity in postsynaptic neurons, indicating that it is mediated by presynaptic mechanisms. Presynaptic mGluRs could function as autoreceptors and regulate the amount of glutamate released. The presynaptic inhibition does not appear to involve a reduction of calcium influx since mGluR agonists that reduce synaptic transmission do not reduce the calcium current, nor do they affect the calcium component of reticulospinal action potentials. Thus, these results indicate that mGluRs depress synaptic transmission by acting directly on the release machinery.

Postsynaptically, activation of the group I mGluRs induces calcium oscillations and potentiates the NMDA-induced current. Calcium oscillations are mediated by calcium release from internal stores through a mechanism dependent on calcium influx through L-type channels. These oscillations are blocked by a specific mGluR5 antagonist. The potentiation of the NMDA-induced current is mediated through activation of G-proteins and is blocked by an antagonist acting on mGluR I. Blockade of this receptor decreases the locomotor burst frequency, indicating that this mGluR subtype is activated by endogenous release of glutamate during NMDA-induced locomotor activity. The interaction between mGluR1 and NMDA receptors could represent a mechanism by which group I mGluRs regulate the locomotor burst frequency. Computer simulations of the interaction between these two receptors reproduced both the modulation of NMDA-induced responses and the increase in the locomotor frequency, further supporting the interactive role of mGluRs and NMDA receptors in regulating locomotor activity.

Glutamate mediates fast synaptic transmission through ionotropic glutamate receptors, but the variety of mGluRs and their cellular distribution provide a mechanism by which glutamate may also act on a slower time scale to modulate the spinal network underlying locomotion.

List of scientific papers

I. Krieger P, el Manira A, Grillner S (1996). "Activation of pharmacologically distinct metabotropic glutamate receptors depresses reticulospinal-evoked" J Neurophysiol 76(6): 3834-41
https://pubmed.ncbi.nlm.nih.gov/97138897

II. Krieger P, Buschges A, el Manira A (1999). "Calcium channels involved in synaptic transmission from reticulospinal axons in lamprey" J Neurophysiol 81(4): 1699-705
https://pubmed.ncbi.nlm.nih.gov/99218195

III. Krieger P, Manira A (2000). "Group III mGluR-mediated depression of sensory synaptic transmission" (Manuscript)

IV. Krieger P, Grillner S, El Manira A. (1998). "Endogenous activation of metabotropic glutamate receptors contributes to burst frequency regulation in the lamprey locomotor network." Eur J Neurosci 10(11): 3333-42
https://pubmed.ncbi.nlm.nih.gov/99046832

V. Krieger P, Hellgren-Kotaleski J, Kettunen P, El Manira AJ (2000). "Interaction between metabotropic and ionotropic glutamate receptors regulates neuronal network activity" J Neurosci 20(14): 5382-91
https://pubmed.ncbi.nlm.nih.gov/20341893

VI. Kettunen P, Krieger P, Manira A (2000). "Signaling mechanisms of group I mGluRs in lamprey spinal cord neurons" (Manuscript)