Comparison of Metabotropic Glutamate Receptor Responses at Segmental and Descending Inputs to Motoneurons in Neonatal Rat Spinal Cord

Abstract

We compared the contribution of metabotropic glutamate receptors (mGluRs) to the generation and modulation of synaptic responses elicited in intracellularly recorded L5 motoneurons from neonatal rats by segmental and descending fibers. Dorsal root (DR) stimulation at high intensity (C-fiber strength) evoked long latency (2-5-s) depolarization in addition to early monosynaptic and polysynaptic responses. Stimulation of the descending ventrolateral funiculus (VLF) failed to evoke a late response in the same motoneuron. The mGluR antagonist (ϩ)-␣-methyl-4-carboxyphenylglycine (MCPG; 0.4 mM) selectively blocked the long latency DR response. This mGluR-mediated response persisted in ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate or N-methyl-D-aspartate (NMDA) antagonists, but not both, suggesting that glutamate transmission (either AMPA/kainate or NMDA) is required for mGluR-mediated inputs from small diameter sensory afferents to affect the motoneuron. Although MCPG inhibited the long latency DR response, it induced moderate facilitation of monosynaptic DR and VLF responses. The mGluR agonist 1s3r-ACPD induced motoneuron depolarization and depressed the monosynaptic DR and VLF responses. MCPG also facilitated the neurotrophin-3 and brain-derived neurotrophic factor induced strengthening of the monosynaptic DR responses (but only before P6, since neurotrophins are ineffective later at DR synapses and never at VLF synapses after birth). Our results suggest that mGluRs are involved in synaptic pathways to motoneurons made by DR but not VLF fibers. MCPG-induced facilitation of monosynaptic AMPA/kainate DR and VLF responses suggests the possibility of tonic mGluR-mediated inhibition of DR and VLF responses. We speculate that MCPG facilitates neurotrophin-induced strengthening of monosynaptic DR responses by reducing this tonic inhibition.Lumbar motoneurons in neonatal rat spinal cord receive excitatory synaptic inputs from two major pathways: a segmental pathway that can be activated by electrical stimulation of the corresponding dorsal root (DR) and a descending pathway activated by stimulation of ventrolateral funiculus (VLF) axons (Pinco and Lev-Tov, 1994). Both these pathways elicit monosynaptic EPSPs via AMPA/kainate receptors. They also activate NMDA receptors, but this action is more complex since the properties of NMDA receptors on motoneurons change markedly during early postnatal development (Arvanian and Mendell, 2001a;Arvanian et al., 2004a) becoming more subject to Mg 2ϩ block at resting membrane potential. Of considerable interest is the fact that the NMDA receptors associated with VLF inputs mature earlier than those associated with DR inputs on the same motoneuron (Arvanian et al., 2004a).A third group of receptors activated by glutamate is the metabotropic class of glutamate receptors (for review, see Schoepp and Conn, 2002). Previous investigators have demonstrated a metabotropic component of DR-evoked responses in motoneurons (Jane et al

Developmentally Regulated Modulation of Lumbar Motoneurons by Metabotropic Glutamate Receptors: A Cellular and Behavioral Analysis in Newborn Mice

“…The present investigation as well as previous studies, have demonstrated that neither broad spectrum nor specific mGluR antagonists have significant effects per se on spinal MNs or VLF-MN synapses (Marchetti et al, 2003;Arvanian et al, 2005;Iwagaki and Miles, 2011) suggesting an absence of endogenous, tonically activated mGluRs. Here, we show that mGluR activation can be induced by increasing synaptic glutamate concentration with the glutamate uptake blocker TBOA or high frequency stimulation of presynaptic axons that revealed the extrasynaptic localization of mGluRs at synapses impinging onto lumbar MNs.…”

“…As previously shown by our group ( Lenschow et al, 2016 ), VLF-EPSCs exhibit paired-pulse facilitation (PPF) with this stimulation paradigm ( Figures 1A1–A3 ). In 1 week old rat pups, MCPG, a broad spectrum mGluR antagonist has been shown to block the late component of dorsal root response in lumbar MNs but failed to affect VLF-induced responses ( Arvanian et al, 2005 ). We observed a similar lack of effect of 200 μM MCPG on both VLF-EPSC amplitude ( Figures 1A1,A4 ) and the PPF ratio (VLF-EPSC2/VLF-EPSC1 = 1.3 ± 0.3 in control condition and 1.3 ± 0.3, n = 18 in the presence of MCPG, p = 0.5, Wilcoxon matched-pairs test) in P1-P3 mice.…”

Input‐specific plasticity of N‐methyl‐d‐aspartate receptor‐mediated synaptic responses in neonatal rat motoneurons

“…In evaluating glutamatergic transmission, it is important to recognize that the initial response measured intracellularly from motoneurons consists of two components, one mediated by α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA)/kainate receptors, and a slightly slower one mediated by N ‐methyl‐ d ‐aspartate (NMDA) receptors (NMDARs) (Ziskind‐Conhaim, 1990; Arvanian & Mendell, 2001a). A third component, mediated by metabotropic glutamate receptors, appears much later, and requires high‐intensity stimuli activating C‐fibers (Arvanian et al. , 2005).…”