Pharmacology of postsynaptic metabotropic glutamate receptors in rat hippocampal CA1 pyramidal neurones

Abstract

Activation of metabotropic glutamate receptors (mGluRs) in hippocampal CA1 pyramidal neurones leads to a depolarization, an increase in input resistance and a reduction in spike frequency adaptation (or accommodation). At least eight subtypes of mGluR have been identified which have been divided into three groups based on their biochemical, structural and pharmacological properties. It is unclear to which group the mGluRs which mediate these excitatory effects in hippocampal CA1 pyramidal neurones belong. We have attempted to address this question by using intracellular recording to test the effects of a range of mGluR agonists and antagonists, that exhibit different profiles of subtype specificity, on the excitability of CA1 pyramidal neurones in rat hippocampal slices (2S,1′S,2′S)‐2‐(2′‐carboxycyclopropyl)glycine (L‐CCG1) caused a reduction in spike frequency adaptation and a depolarization (1–10 mV) associated with an increase in input resistance (10–30%) at concentrations (≥50 μm) that have been shown to activate mGluRs in groups I, II and III. Similar effects were observed with concentrations (50–100 μm) of (1 Inhibition of the release of endogenous neurotransmitters through activation of GABAB receptors, by use of 200 μm (±)‐baclofen, did not alter the effects of (1S,3R)‐ACPD (50‐100 μm) (1S,3S)‐ACPD (100 μm) or L‐CCG1 (100 μm). This suggests that mGluR agonists directly activate CA1 pyramidal neurones. Like these broad spectrum mGluR agonists, the racemic mixture ((SR)‐) or resolved (S)‐isomer of the selective group I mGluR agonist 3,5‐dihydroxyphenylglycine ((SR)‐DHPG (50‐100 μm) or (S)‐DHPG (20‐50μm)) caused a reduction in spike frequency adaptation concomitant with postsynaptic depolarization and an increase in input resistance. In contrast, 2S,1′R,2′R,3′R‐2‐(2′,3′‐dicarboxycyclo‐propyl)glycine (DCG‐IV; 100 μm) and (S)‐2‐amino‐4‐phosphonobutanoic acid (L‐AP4; 100‐500 μm), which selectively activate group II mGluRs and group III mGluRs, respectively, had no effect on the passive membrane properties or spike frequency adaptation of CA1 pyramidal neurones. The mGluR antagonists (+)‐α‐methyl‐4‐carboxyphenylglycine ((+)‐MCPG; 1000 μm) and (S)‐4‐carboxyphenylglycine ((S)‐4CPG; 1000 μm), which block groups I and II mGluRs and group I mGluRs, respectively, had no effect on membrane potential, input resistance or spike frequency adaptation per se. Both of these antagonists inhibited the postsynaptic effects of (1S,3R)‐ACPD (50‐100 μm), (1S,3S)‐ACPD (30‐100 μm) and L‐CCG1 (50‐100 μm). (+)‐MCPG also reversed the effects of (SR)‐DHPG (75 μm). (The effect of (S)‐4CPG was not tested.) Their action was selective in that both antagonists did not reverse the reduction in spike frequency adaptation induced by carbachol (1 μm) or noradrenaline (10 μm) whereas atropine (10 μm) and propranolol (100 μm) did. From these data it is concluded that the mGluRs in CA1 pyramidal neurones responsible for these excitatory effects are similar to the mGluRs expressed by non‐neuronal cells transfected with cDNA encoding group I mGluRs.

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…Activity-dependent LTD of EPSC AMPA and EPSC NMDA that relies on mGlu receptors has been described at Schaffer collateral-CA1 synapse [26][27][28]. Here, using whole-cell patch clamp recordings, we confirm previous data showing that mGlu-LTD of both EPSC AMPA and EPSC NMDA transmission can be induced pharmacologically at CA1 hippocampal synapses.…”

“…Thus, we extended our analysis investigating the potential contribution of ASIC1a in modulating DHPG-mediated increase of firing discharge induced by depolarizing current steps [28]. Fig.…”

“…3A). Next, we studied the effect of PcTx1 on the enhancement of firing discharge induced by group I mGlu receptors activation [28,31,32]. Accordingly, bath-applied DHPG (50 M, 10 min) increases the number of APs evoked by depolarizing current pulses (n = 7, 350 pA p < 0,05; 50 pA p < 0,05; −250 pA p > 0.05) and this leads also to a significant enhancement of total postsynaptic depolarization as measured by the area under the curve (n = 7, 350 pA p < 0.05; 50 pA p < 0.01; −250 pA p > 0.05).…”

Postnatal maturational properties of rat parafascicular thalamic neurons recorded in vitro

“…These changes might reflect the maturation of voltage-dependent conductances underlying AP generation and/or a corresponding developmental change in the afferent input to Pf cells. For example, AP-frequency accommodation mediated by calcium-activated potassium conductances can be blocked by activation of different neurotransmitter receptors, including acetylcholine, serotonin, norepinephrine and metabotropic glutamate receptors (Malenka et al, 1986;Andrade and Nicoll, 1987;McCormick et al, 1991;Davies et al, 1995). Developmental changes in neurotransmitter-specific afferent inputs to Pf during this early postnatal period, especially as it relates to modulation of cell firing, remains an unexplored area of research.…”

Interaction between Ephrins and mGlu5 Metabotropic Glutamate Receptors in the Induction of Long-Term Synaptic Depression in the Hippocampus

“…We challenged the slices with DHPG at concentrations of 10 M to induce a transient depression of synaptic transmission. Lower concentrations of DHPG (5 M) did not affect synaptic transmission (data not shown; see also van Dam et al, 2004), whereas higher concentrations (20 -50 M) are known to induce postsynaptic depolarization (Davies et al, 1995) and nondecremental LTD (Palmer et al, 1997;Fitzjohn et al, 1999). In adult hippocampal slices, bath application of 10 M DHPG for 20 min induced a short-term depression (STD) of synaptic activity (from 18 to 42% below the baseline in different experiments) that returned back to baseline levels 30 min following washout of DHPG (Fig.…”