Activation of group I metabotropic glutamate receptors enhances efficacy of glutamatergic inputs to neonatal rat hypoglossal motoneurons in vitro

Abstract

Group I metabotropic glutamate receptors (mGluRs) are the main class of metabotropic receptors expressed in the hypoglossus nucleus. Their role in glutamatergic transmission was investigated using patch-clamp recording from motoneurons in a neonatal rat brainstem slice preparation. After pharmacological block of gamma-aminobutyric acid and glycine-mediated inhibition, under voltage-clamp, the selective group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) induced a motoneuron inward current by depressing a leak conductance, and strongly facilitated spontaneous glutamatergic synaptic currents. This effect was blocked by 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) and unaffected by 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), indicating a role for subtype 1 mGluRs. The frequency but not the amplitude of miniature glutamatergic currents was also enhanced by DHPG. Currents elicited by puffer application of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the presence of tetrodotoxin were also unchanged, suggesting that DHPG facilitated release of glutamate. Glutamatergic currents evoked by electrically stimulating the dorsomedullary reticular column premotoneurons were, however, depressed by DHPG in a CPCCOEt-sensitive fashion. Neither CPCCOEt nor MPEP per se changed glutamatergic transmission. Under current-clamp, even if DHPG depressed excitatory postsynaptic potentials, motoneuron spike threshold and time to peak were reduced so that facilitation of synaptic potential/spike coupling became apparent. We propose a wiring diagram to account for the differential action by DHPG on spontaneous and evoked transmission, based on the discrete distribution of subtype 1 mGluRs on glutamatergic afferents. Although under standard recording conditions there was insufficient ambient glutamate to activate mGluRs, such receptors were a powerful target to upregulate excitatory synaptic transmission and enhance signalling by hypoglossal motoneurons to tongue muscles.

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

“…These effects of CDPPB may be direct, as the activation of mGlu5 receptors produces excitatory postsynaptic potentials (EPSP) in vitro (Fitzjohn et al 1999;Sharifullina et al 2004;Wisniewski and Car 2002), or indirect through increasing the efficacy of endogenous glutamate neurotransmission at NMDA receptors. For example, positive allosteric modulation of mGlu5 receptors has been shown to enhance phosphorylation of the NR1 subunit of the NMDA receptors and the expression of signaling molecules such as cyclic adenosine monophosphate (cAMP) response element-binding (CREB) and extracellular signal-regulated kinase (ERK), all of which are critical for glutamate-mediated signal transduction mechanisms (Liu et al 2006).…”

Developmental regulation of membrane excitability in rat spinal lamina I projection neurons

“…The numbers of animals used were the same as described in Fig. 2. age-dependent reduction in AP threshold, which would be predicted to facilitate synaptic potential-spike coupling (Andersen et al 1980;Sharifullina et al 2004) and thus enhance the effectiveness of nociceptive inputs to these neurons. Spike duration also decreased with age in both groups (Fig.…”

Dopaminergic Modulation of Spinal Neuronal Excitability

“…DA was then bath applied for a duration of 5 min before washing out. The peak amplitude was calculated and a first-order exponential function was applied to the decay phase of the EPSC to determine the time constant (Sharifullina et al, 2004).…”

“…6 B). To further test for postsynaptic effects, we applied puffs of AMPA (one puff every minute), before, during, and after washout of bath-applied DA, using previously published protocols (Sharifullina et al, 2004). To reduce space clamp concerns and block K ϩ conductances, we added Cs ϩ to the intracellular pipette solution.…”