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

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.

SUBMITTER: Ster J

PROVIDER: S-EPMC3116403 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Ster Jeanne J Mateos José María JM Grewe Benjamin Friedrich BF Coiret Guyllaume G Corti Corrado C Corsi Mauro M Helmchen Fritjof F Gerber Urs U

Proceedings of the National Academy of Sciences of the United States of America 20110531 24

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 c ...[more]

PMID: 21628565

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Project description:We examined the expression of metabotropic glutamate (mGlu) receptors in species of fish that differ for their vulnerability to anoxic brain damage. Although expression of mGlu1a and mGlu5 receptors was similar in the brain of all species examined, expression of mGlu2/3 receptors was substantially higher in the brain of anoxia-tolerant species (i.e., the carp Carassius carassius and the goldfish Carassius auratus) than in the brain of species that are highly vulnerable to anoxic damage, such as the trouts Salmo trutta and Oncorhynchus mykiss. This difference was confirmed by measuring the mGlu2/3 receptor-mediated inhibition of forskolin-stimulated cAMP formation in slices prepared from the telencephalon of C. auratus and S. trutta. We exposed the goldfish C. auratus to water deprived of oxygen for 4 hr for the induction of hypoxic brain damage. Although the goldfish survived this treatment, the occurrence of apoptotic cell death could be demonstrated by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and by the assessment of caspase-3 activity in different brain region. The extent of cell death was highest in the medulla oblongata, followed by the optic tectum, cerebellum, and hypothalamus. No cell death was found in the telencephalon. This regional pattern of hypoxic damage was inversely related to the expression of mGlu2/3 receptors, which was lowest in the medulla oblongata and highest in the telencephalon. Treatment of the goldfish with the brain permeant mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.) amplified anoxic damage throughout the brain and enabled the induction of cell death by anoxia in the telencephalon. In contrast, treatment of the goldfish with the mGlu2/3 receptor agonist LY379268 (0.5 or 1 mg/kg, i.p.) was highly protective against anoxic brain damage. Finally, exposure to the antagonist LY341495 (0.5 microm) greatly amplified the release of glutamate induced by hypoxia in slices prepared from the medulla oblongata and the telencephalon of the goldfish. We conclude that expression of mGlu2/3 receptors provides a major defensive mechanism against brain damage in anoxia-tolerant species.

Project description:It is well established that selective activation of group I metabotropic glutamate (mGlu) receptors induces LTD of synaptic transmission at Schaffer collateral-CA1 synapses. In contrast, application of 1S,3R-ACPD, a mixed agonist at group I and group II mGlu receptors, induces LTP. Using whole-cell recordings from CA1 pyramidal cells and field recordings in the hippocampal CA1 region, we investigated the specific contribution of group II mGlu receptors to synaptic plasticity at Schaffer collateral-CA1 synapses in acute slices of adult mice. Pharmacological activation of group II mGlu receptors (mGlu2 and mGlu3 receptors) with the specific agonist LY354740 in conjunction with electrical stimulation induced postsynaptic LTP. This form of plasticity requires coactivation of NMDA receptors (NMDARs). Group II mGlu receptor activation led to PKC-dependent phosphorylation of the GluN1 subunit. We found that both synaptic and extrasynaptic NMDARs, which are differentially modulated by mGlu2 and mGlu3 receptors, contribute to LTP induction. Furthermore, LTP initiated by activation of group II mGlu receptors was not occluded by LTP induced with high-frequency trains of stimuli. However, the phosphorylation of NMDARs mediated by group II mGlu receptor activation led to a priming effect that enhanced subsequent high-frequency stimulation-induced LTP. These findings reveal a novel metaplastic mechanism through which group II mGlu receptors modulate synaptic function at the Schaffer collateral input to CA1 pyramidal cells, thereby lowering the threshold to induce plasticity.Significance statementThe group II metabotropic glutamate (mGlu II) receptors exert a well characterized action on presynaptic neuron terminals to modulate neurotransmitter release. Here, we show that these receptors also have postsynaptic effects in promoting the induction of synaptic plasticity. Using an electrophysiological approach including field and whole-cell patch recording in hippocampi from wild-type and transgenic mice, we show that activation of group II mGlu receptors enhances NMDA receptor (NMDAR)-mediated currents through PKC-dependent phosphorylation. This priming of NMDARs lowers the threshold for the induction of LTP of synaptic transmission. These findings may also provide new insights into the mechanisms through which drugs targeting mGlu II receptors alleviate hypoglutamatergic conditions such as those occurring in certain brain disorders such as schizophrenia.

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

Publications

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

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