ly-341495 and (alpha-carboxycyclopropyl)glycine

The subiculum (SUB) is a pivotal structure positioned between the hippocampus proper and various cortical and subcortical areas. Despite the growing body of anatomical and intrinsic electrophysiological data of subicular neurons, modulation of synaptic transmission in the SUB is not well understood. In the present study we investigated the role of group II metabotropic glutamate receptors (mGluRs), which have been shown to be involved in the regulation of synaptic transmission by suppressing presynaptic cAMP activity. Using field potential and patch-clamp whole cell recordings we demonstrate that glutamatergic transmission at CA1-SUB synapses is depressed by group II mGluRs in a cell-type specific manner. Application of the group II mGluR agonist (2S,1'R,2'R,3'R)-2-(2, 3-dicarboxycyclopropyl)glycine (DCG-IV) led to a significantly higher reduction of excitatory postsynaptic currents in subicular bursting cells than in regular firing cells. We further used low-frequency stimulation protocols and brief high-frequency bursts to test whether synaptically released glutamate is capable of activating presynaptic mGluRs. However, neither frequency facilitation is enhanced in the presence of the group II mGluR antagonist LY341495, nor is a test stimulus given after a high-frequency burst. In summary, we present pharmacological evidence for presynaptic group II mGluRs targeting subicular bursting cells, but both low- and high-frequency stimulation protocols failed to activate presynaptically located mGluRs.

Topics: Amino Acids; Amino Acids, Dicarboxylic; Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Cyclopropanes; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Glycine; Hippocampus; Male; Neurons; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Synaptic Transmission; Xanthenes

Mossy fiber long-term depression (LTD) has been shown to be triggered by either pharmacological or synaptic activation of Group II metabotropic glutamate receptors (mGluRs) whereas other studies indicate that synaptic activation of mGluRs is very limited. Therefore, we reexamined the role of Group II mGluRs for the induction of mossy fiber LTD. The complete depression of field potentials (fEPSPs) by 1 microM (2S,2'R,3'R)-2-(2',3'-Dicarboxycyclopropyl)glycine (DCG-IV) only partially reversed upon removal of the drug but fEPSPs were completely restored by the Group II antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495) (3 microM). In contrast, fEPSPs returned back to baseline within 30 min after a brief application of 0.2 microM DCG-IV suggesting that the incomplete reversal of higher concentrations may be due to a residual receptor occupancy rather than to an induction of LTD. LY341495 itself did not increase fEPSPs and also blocked the inhibition of (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine (L-CCG-I) (20 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) (10 microM) and its effect was mimicked by CPPG (50 microM). Furthermore, stimulation at 1 Hz for 15 min induced an LTD of 81% +/- 3% and 80% +/- 4% in the absence and presence of LY341495, respectively (n = 7, 5). Finally, we found that synaptic activation of Group II mGluRs during 15 min of 1-Hz stimulation only produces an inhibition of release by 8% +/- 1% (30 degrees C, n = 3). Our data suggests that pharmacological activation of Group II mGluRs is fully reversible per se and does not produce a long lasting depression and that activation of Group II mGluRs is neither necessary nor sufficient for the induction of mossy fiber LTD.

Topics: Amino Acids; Amino Acids, Dicarboxylic; Animals; Cycloleucine; Cyclopropanes; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glycine; Hippocampus; In Vitro Techniques; Long-Term Synaptic Depression; Mice; Mice, Inbred C57BL; Neural Inhibition; Neurons; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Synaptic Transmission; Xanthenes

Patch pipettes were used to record currents in whole-cell configuration to study the effects of group II metabotropic glutamate receptor (mGluR) stimulation on synaptic transmission in slices of rat subthalamic nucleus. Evoked glutamatergic excitatory postsynaptic currents (EPSCs) were reversibly reduced by the selective group II mGluR agonist (2'S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) in a concentration-dependent manner, with an IC50 of 0.19 +/- 0.05 microM. DCG IV (1 microM) had no effect on inhibitory postsynaptic currents mediated by GABA. DCG IV-induced inhibition of EPSCs was reversed by the selective group II mGluR antagonist LY 341495 (100 nM) and mimicked by another selective group II agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). Inhibition of EPSC amplitude by DCG IV and L-CCG-I was associated with an increase in the paired-pulse ratio of EPSCs. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (2 microM) reduced the inhibitory effect of DCG IV on EPSCs. However, the response to DCG IV was not affected by the protein kinase A (PKA) activator forskolin (20 microM), by the adenylyl cyclase inhibitor MDL 12230A (20 microM), or by the phosphodiesterase inhibitor Ro 20-1724 (50 microM). DCG IV-induced inhibition of EPSCs was reduced by the non-selective protein kinase inhibitors H-7 (100 microM), H-8 (50 microM) and HA-1004 (100 microM). These results suggest that group II mGluR stimulation acts presynaptically to inhibit glutamate release by a PKC-dependent mechanism in the subthalamic nucleus.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 2-Amino-5-phosphonovalerate; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; 6-Cyano-7-nitroquinoxaline-2,3-dione; Adenylyl Cyclase Inhibitors; Amino Acids; Amino Acids, Dicarboxylic; Animals; Colforsin; Cyclopropanes; Electric Stimulation; Electrophysiology; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Glycine; Imines; In Vitro Techniques; Isoquinolines; Male; Picrotoxin; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Subthalamic Nucleus; Sulfonamides; Synaptic Transmission; Tetradecanoylphorbol Acetate; Xanthenes