Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors - PubMed (original) (raw)

Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors

Jeanne Ster et al. Proc Natl Acad Sci U S A. 2011.

Abstract

Impaired function or expression of group II metabotropic glutamate receptors (mGluRIIs) is observed in brain disorders such as schizophrenia. This class of receptor is thought to modulate activity of neuronal circuits primarily by inhibiting neurotransmitter release. Here, we characterize a postsynaptic excitatory response mediated by somato-dendritic mGluRIIs in hippocampal CA3 pyramidal cells and in stratum oriens interneurons. The specific mGluRII agonists DCG-IV or LCCG-1 induced an inward current blocked by the mGluRII antagonist LY341495. Experiments with transgenic mice revealed a significant reduction of the inward current in mGluR3(-/-) but not in mGluR2(-/-) mice. The excitatory response was associated with periods of synchronized activity at theta frequency. Furthermore, cholinergically induced network oscillations exhibited decreased frequency when mGluRIIs were blocked. Thus, our data indicate that hippocampal responses are modulated not only by presynaptic mGluRIIs that reduce glutamate release but also by postsynaptic mGluRIIs that depolarize neurons and enhance CA3 network activity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Stimulation of mGluRIIs increases synaptic activity recorded from CA3 pyramidal cells in acute as well as in cultured hippocampal slices. (A) DCG-IV (2 μM) increases amplitude and frequency of EPSCs and IPSCs in slice culture. (Lower) Expanded traces of spontaneous activity in the absence (1) and in the presence of DCG-IV (2). (B) Effects of DCG-IV in an acute slice. (C) Quantification of spontaneous activity (black: EPSCs; gray: IPSCs) induced by DCG-IV and LCCG-1 in cultured slices (CS) or acute slices (AS). (D) Subcellular localization of mGluR2/3 in the CA3 area of hippocampal slice cultures. mGluR2/3 is expressed in the preterminal region and along the length of axons (arrow). Asterisks indicate postsynaptic mGluR2/3 in dendrites in CA3 neurons. (Scale bars: 0.2 μm.)

Fig. 2.

Fig. 2.

DCG-IV applied to CA3 pyramidal cells induces inward current associated with a decrease in potassium and an increase in cationic conductance. (A) Upper trace shows inward current induced by DCG-IV (2 μM, 10 min) in a CA3 pyramidal cell voltage clamped at −70 mV in the presence of TTX and picrotoxin. (B) Quantification of inward current induced by DCG-IV, by DCG-IV in the presence of the group II antagonist LY341495 or an NMDAR antagonist D-AP5, by LCCG-1, and by LCCG-1 in presence of D-AP5 or LY341495 (Left); quantification of inward current induced by DCG-IV in wild type (WT), mGluR2−/−, and mGluR3−/− mice (Right). (C) Subtracted I/V relationships (Left) in rat pyramidal cells obtained with voltage steps incrementing by 10-mV steps indicating (filled circles) a reduction in K conductance when measured with a K+-based intracellular medium and (open circles) an increase in a cationic conductance with a Cs+-based intracellular medium (n = 6). (Right) Current traces from a representative experiment obtained in the presence of DCG-IV (black line) or in the presence of DCG-IV and CPA (gray line) with a K+-based intracellular medium (Top) or with a Cs+-based intracellular medium (Bottom).

Fig. 3.

Fig. 3.

Calcium responses mediated by mGluRIIs. (A) A barrage of calcium transients evoked by LCCG-1 in a CA3 pyramidal cell. (B) In current clamp mode, LCCG-1 induces a depolarization resulting in action potential firing, accompanied by an increase in synaptic noise. (C) Addition of TTX blocks calcium spikes but not the maintained calcium rise induced by LCCG-1. Emptying calcium stores with CPA reduces the calcium rise. (D) Histogram represents the mean Δ_F_/F (%) to illustrate the effect of CPA.

Fig. 4.

Fig. 4.

Activating mGluRIIs synchronizes network activity. (A) (Upper) LCCG1 (10 μM, 10 min) in rat slice cultures increases synaptic activity in two unconnected pyramidal cells leading to synchronized synaptic events. (Lower) Cross-correlograms of spontaneous synaptic activity in the two cells during control (Left) and in the presence of LCCG-1 (Right). (B) Methacholine (500 nM) induces oscillations that are significantly decreased by the group II mGluR antagonist LY341495 (n = 5). (C) LCCG1 (10 μM, 10 min) induces oscillations of the same frequency in wild type (WT) and in mGluR2−/−, but at lower frequency in mGluR3−/− mice.

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