Activation of Presynaptic Group III Metabotropic Receptors Enhances Glutamate Release in Rat Entorhinal Cortex

Abstract

The role of group III metabotropic glutamate receptors (mGluRs) in modulating excitatory synaptic transmission was investigated in the rat entorhinal cortex (EC) in vitro. AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) were recorded in the whole cell configuration of the patch-clamp technique from visually identified neurons in layers V and II. In layer V, bath application of the specific group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 500 microM) resulted in a marked facilitation of both spontaneous and activity-independent "miniature" (s/mEPSC) event frequency. The facilitatory effect of L-AP4 (100 microM) on sEPSC frequency prevailed in the presence of DL-2-amino-5-phosphonopentanoic acid (100 microM) but was abolished by the group III antagonist (RS)-cyclopropyl-4-phosphonophenylglycine (20 microM). These data confirmed that group III mGluRs, and not N-methyl-D-aspartate (NMDA) receptors were involved in the response to L-AP4. Bath application of the specific mGluR4a agonist (1S,3R,4S)-1-aminocyclopentane-1,2, 4-tricarboxylic acid (20 microM) also had a facilitatory effect on sEPSC frequency, suggesting involvement of mGluR4a. In layer II neurons, L-AP4 caused a reduction in sEPSC frequency but did not affect mEPSCs recorded in the presence of tetrodotoxin. These findings suggest that a group III mGluR with mGluR4a-like pharmacology is involved in modulating synaptic transmission in layer V cells of the EC. The effect on mEPSCs suggests that this receptor is located presynaptically and that its activation results in a direct facilitation of glutamate release. This novel facilitatory effect is specific to layer V and, to our knowledge, is the first report of a direct facilitatory action of group III mGluRs on synaptic transmission. In layer II, L-AP4 had an inhibitory effect on glutamate release similar to that reported in other brain regions.

Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus

“…The complement of different group III mGluRs at distinct synapses plays a differential role in determining the specific physiological behavior of neuronal responses Scanziani et al, 1998;Evans et al, 2000;Semyanov and Kullmann, 2000). For example, in the hippocampal CA1 area, high levels of mGluR4 (Corti et al, 2002;Kogo et al, 2004), mGluR7a (Shigemoto et al, , 1997Kogo et al, 2004), and mGluR7b are present in the presynaptic active zone of distinct sets of synapses with different dynamics.…”

Group III Metabotropic Glutamate Receptors Maintain Tonic Inhibition of Excitatory Synaptic Input to Hypocretin/Orexin Neurons

“…Group III metabotropic receptors (mGluRs) have been found in many regions of the brain (Bradley et al, 1998;Evans et al, 2000;Awatramani and Slaughter, 2001;Losonczy et al, 2003;Valenti et al, 2003), including the hypothalamus (Meeker et al, 1994;Ghosh et al, 1997;Schrader and Tasker, 1997;Chen and van den Pol, 1998;van den Pol et al, 1998b) and include mGluR4, mGluR6, mGluR7, and mGluR8. Activation of these mGluRs activates G i /G o -proteins, causing a decrease in cAMP, and modulates synaptic activity by altering phosphorylation of ion channels, receptors, and second-messenger systems (Nakanishi, 1994;Cartmell and Schoepp, 2000;Schoepp, 2001).…”

“…In other regions of the brain, activation of group III mGluRs has been reported to inhibit selectively GABAergic neurons, and this disinhibition led to an increase in circuit activity (Semyanov and Kullmann, 2000). Group III mGluRs have also been reported to enhance directly glutamate release in layer 5 of the cortex (Evans et al, 2000) or to attenuate glutamate responses by a direct postsynaptic mechanism in the nucleus accumbens (Taverna and Pennartz, 2003).…”

Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7

“…However, mGluR7 is also present at inhibitory nerve terminals, and inhibition of such terminals should produce excitation due to a reduced release of GABA. Consistent with such a mechanism, activation of group III mGluRs has been found to facilitate glutamate release in some layers of the cortex (39). Also, glutamate spillover resulting from mossy fiber stimulation in cerebellar glomeruli has been shown to suppress GABA release via presynaptic mGluR activation (40).…”