Abstract
The present study explores the impact of metabotropic glutamate receptor (mGluR) activation on activity-dependent synaptic plasticity (ADSP) and the intrinsic membrane properties of lumbar motoneurons (MNs) using a combination of biochemical, pharmacological, electrophysiological and behavioral techniques. Using spinal cord slices from C57BL/6JRJ mice at two developmental stages, 1-3 and 8-12 postnatal days (P1-P3; P8-P12, respectively), we found that ADSP expressed at glutamatergic synapses between axons conveyed in the ventrolateral funiculus (VLF) and MNs, involved mGluR activation. Using specific agonists of the three groups of mGluRs, we observed that mGluR stimulation causes subtype-specific and developmentally regulated modulation of the ADSP and synaptic transmission at VLF-MN synapses as well as the intrinsic membrane properties of MNs. RT-qPCR analysis revealed a downregulation of mGluR gene expression with age in the ventral part of the lumbar spinal cord. Interestingly, the selective harvest by laser microdissection of MNs innervating the Gastrocnemius and Tibialis anterior muscles unraveled that the level of Grm2 expression is higher in Tibialis MNs compared to Gastrocnemius MNs suggesting a specific mGluR gene expression profile in these two MN pools. Finally, we assessed the functional impact of mGluR modulation on electrically induced bouts of fictive locomotion in the isolated spinal cord preparation of P1-P3 mice, and in vivo during spontaneous episodes of swimming activity in both P1-P3 and P8-P12 mouse pups. We observed that the mGluR agonists induced distinct and specific effects on the motor burst amplitudes and period of the locomotor rhythms tested and that their actions are function of the developmental stage of the animals. Altogether our data show that the metabotropic glutamatergic system exerts a complex neuromodulation in the developing spinal lumbar motor networks and provide new insights into the expression and modulation of ADSP in MNs.
Highlights
After providing the first evidence that flexor and extensor MNs exhibit different types of activity-dependent synaptic plasticity (ADSP) after high frequency stimulation (HFS) at ventrolateral funiculus (VLF)-MN synapses (Lenschow et al, 2016), the present study identified a differential modulation of ADSP by glutamate through the activation of metabotropic glutamate receptor (mGluR) that is synchronized to a high expression of mGluR genes (Grm) genes in mouse lumbar MNs during the first postnatal week
We show that mGluR activation can be induced by increasing synaptic glutamate concentration with the glutamate uptake blocker DL-threo-benzyloxyaspartic acid (TBOA) or high frequency stimulation of presynaptic axons that revealed the extrasynaptic localization of mGluRs at synapses impinging onto lumbar MNs
Associated with the results we obtained on MN membrane properties and synaptic transmission, this study further indicates that mGluRII and mGluRIII are located on both the pre- and postsynaptic sides of the VLF-MN synapses and act as inhibitory autoreceptors at the two developmental stages tested
Summary
The main excitatory neurotransmitter of the central nervous system (CNS) acts via four types of ionotropic receptors (N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA), Kainate and Delta receptors) (Madden, 2002; Traynelis et al, 2010) and eight metabotropic glutamate receptors (mGluRs) (Niswender and Conn, 2010; Reiner and Levitz, 2018). mGluRs can be subdivided into three different families based on sequence homology, G-protein coupling and pharmacological profile: the group I mGluR (mGluR1 and mGluR5) coupled to Gq/11 protein and the mGluR II (mGluR2 and 3) and mGluR III (mGluR4, 7 and 8) associated to Gi/o protein. Linked to intracellular calcium signaling, mGluRs play important roles in many aspects of CNS maturation and are known to display developmentally regulated expression patterns with highest global levels reported in the neonate and juvenile brain and spinal cord (Catania et al, 1994; Berthele et al, 1999; Hubert and Smith, 2004). We asked whether mGluRs participate in ADSP in developing MNs, and more globally, whether mGluR-mediated modulation is developmentally regulated in lumbar MNs. Here, using newborn mice and specific agonists of the different mGluR groups, we demonstrate that (1) mGluRs are involved in ADSP expression at VLF-MN synapses, (2) both ADSP and MN intrinsic membrane properties are differentially and developmentally modulated by the different mGluR subtypes, and (3) MNs exhibit a particular mGluR expression pattern depending on whether they are flexor or extensor related neurons. We assessed the functional impact of mGluR modulation both in vitro in the isolated spinal cord preparation and in vivo in behaving mouse pups during swimming
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