Distinct subtypes of group I metabotropic glutamate receptors on rat spinal neurons mediate complex facilitatory and inhibitory effects

Abstract

While group I glutamate metabotropic (mGlu) receptors show discrete neuronal distribution in the neonatal rat spinal cord, the functional role of their distinct receptor subtypes remains uncertain. Intracellular recording from lumbar motoneurons together with extracellular recording of ventral root (VR) responses was used to investigate the differential contribution by mGlu receptor subtypes to cell excitability and network activity. The group I agonist DHPG evoked motoneuron depolarization (via the AIDA or CPCCOEt-sensitive mGlu receptor subtype 1) mainly at network level and generated sustained, network-dependent oscillations (via the MPEP-sensitive mGlu receptor subtype 5). DHPG also decreased the peak amplitude of synaptic responses induced by dorsal root stimuli, an effect unrelated to depolarization and dependent on glycinergic transmission. Synaptic responses were insensitive to AIDA or MPEP. The present results can be explained by assuming excitation of discrete classes of interneurons by group I mGlu receptor activity. Thus, the cellular distribution of those mGlu receptors at strategic circuit connections may determine the functional outcome of the network in terms of excitation or inhibition. Even if there was insufficient activation by endogenous glutamate of mGlu receptors during synaptic activity evoked by DR stimuli, it is apparent that such receptors are important pharmacological targets for powerful and rapid up- or down-regulation of spinal signal processing at network level, providing a rationale for the proposed use of mGlu receptor agonists in a variety of spinal pathological conditions.

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

“…Consistent with previous reports (King and Liu, 1996), ACPD-induced depolarization was associated with enhanced frequency of spontaneous synaptic potentials and an increase in motoneuron input resistance (56.9 Ϯ 4.3 M⍀ in control and 89.4 Ϯ 5.1 M⍀ in ACPD; n ϭ 5; p Ͻ 0.05). As shown previously with the mGluR1 agonist DHPG (Marchetti et al, 2003), addition of 0.5 M tetrodotoxin, 40 M APV, and 10 M CNQX to restrict the agonist action to the motoneuron reduced the effect of ACPD and blocked the synaptic noise, but some depolarization was still observed (3.4 Ϯ 1.1 mV; n ϭ 4; not illustrated). This suggests that mGluR receptors are located both on motoneurons as well as on cells presynaptic to the motoneuron.…”

“…Since lumbar motoneurons receive inhibitory inputs Lev-Tov, 1993, 1994;Peshori et al, 1998;Vinay and Clarac, 1999), and some of these inputs might interact with mGluRs (Marchetti et al, 2003), we examined whether blockade of inhibitory inputs affected the MCPG-induced facilitation of DR and VLF responses. As shown in Fig.…”

“…Previous investigators have demonstrated a metabotropic component of DR-evoked responses in motoneurons (Jane et al, 1994(Jane et al, , 1995Thompson et al, 1995;King and Liu, 1996;Cao et al, 1997;Marchetti et al, 2003). However, there is no evidence concerning the metabotropic components produced by VLF stimulation.…”

Metabotropic glutamate receptor activity induces a novel oscillatory pattern in neonatal rat hypoglossal motoneurones

“…Fast discharges and slow oscillations were routinely observed in DHPG solution when cells were recorded with an electrode containing the sodium current and I h blocker QX-314 (Marchetti et al 2003; n = 56 out of 92; 61%; see example in Fig. 3A).…”

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

“…Only when repeated network discharges evoke strong release of glutamate, blocking these receptors inhibits electrically induced synaptic transmission (Marchetti et al 2003;Sharifullina et al 2004). These data can suggest two possibilities not mutually exclusive: a fraction of the population of mGluRs is synaptically located (Alvarez et al 2000;Hubert et al 2001;Kuwajima et al 2004), yet because of the intrinsically slow activation process, their contribution to synaptic events comes into action only with sustained neurotransmitter delivery occurs.…”