Group I metabotropic glutamate receptors (mGluRs) play a key role in the mediation of synaptic plasticity in the hippocampus. We have demonstrated previously that, in combination with depolarisation, the specific group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) evokes a somatic supralinear [Ca²⁺]_i response and a simultaneous, but independent, inward current in rat CA1 hippocampal neurons (Rae & Irving, 2001). To date however, the specific role(s) that the group I mGluR subtypes, mGluR1 and mGluR5, play in mediating this combined response has yet to be fully elucidated. Therefore, utilising specific group I mGluR agonists and antagonists, the aim of the present study was to determine the pharmacology underlying these DHPG-evoked supralinear responses.

Experiments were carried out at room temperature on transverse hippocampal slices (350-400 µm) prepared from 14- to 21-day-old rats killed humanely by cervical dislocation. [Ca²⁺]_i measurements were made using conventional epifluorescence Ca²⁺ imaging combined with whole-cell patch-clamp recording by including the calcium-sensitive dye, bis fura-2 (150 µM), in a potassium gluconate-based pipette solution. All experiments were carried out in standard Krebs solution containing TTX (0.5 µM), at -30 mV in order to maximise mGluR responses. Data are expressed as means ± S.E.M.

At -30 mV, DHPG (100 µM; 2 min) evoked a large [Ca²⁺]_i signal in conjunction with a relatively slow inward current. In the presence of the mGluR5 antagonist, 6-methyl-2-(phenylethynyl)-pyridine (MPEP; 10-50 µM), the size of the DHPG-evoked [Ca²⁺]_i signal was reduced by 88.4 ± 4.1 % (P < 0.001; Student’s paired t test) in 14/19 cells. The amplitude of the inward current was also reduced by 43.9 ± 4.5 % (n = 17; P < 0.001). The mGluR1 antagonist, 2-methyl-4-carboxyphenylglycine (LY367385; 100 µM), reduced both the size of the DHPG-evoked [Ca²⁺]_i signal (75.9 ± 6.2% n = 11/13; P < 0.001) and the amplitude of the inward current (50.7 ± 6.5% n = 15/16; P < 0.001). However, MPEP and LY367385 together reduced the inward current by 70.6 ± 6.8 % (n = 4; P < 0.05) and abolished the [Ca²⁺]_i signal. The specific mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 0.5-1 mM) activated an inward current (53.4 ± 11.7 pA, n = 8) in the absence of an increase in [Ca²⁺]_i.

These results suggest that both mGluR1 and mGluR5 contribute to the combined electrical and [Ca²⁺]_i response evoked by DHPG.

This work was supported by the Wellcome Trust and MRC.