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

Ster, Jeanne; Mateos, José Marı́a; Grewe, Benjamin F.; Coiret, Guyllaume; Corti, Corrado; Corsi, Mauro; Helmchen, Fritjof; Gerber, Urs

doi:10.1073/pnas.1100548108

Cited by 33 publications

(39 citation statements)

References 38 publications

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“…This effect is likely due to direct actions of the group II agonist on the postsynaptic neuron, as the experiments were performed in the presence of TTX. Although the exact mechanism by which mGlu 3 , a G i/o coupled receptor, induces intracellular Ca 2+ increases is unknown, similar effects of group II mGlu receptor agonists on intracellular Ca 2+ are observed in hippocampal CA3 pyramidal cell and interneuron populations, and these responses are thought to be mediated by activation of mGlu 3 (29). In addition, there are examples of other G i/o coupled receptors inducing intracellular Ca 2+ elevations (30).…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu 3 ) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu 3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu 3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu 3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu 3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu 3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.etabotropic glutamate receptor 3 (mGlu 3 ) has become of increasing clinical interest due to its genetic association with psychiatric conditions. For example, several studies have identified single-nucleotide polymorphisms (SNPs) in GRM3, the human gene encoding mGlu 3 , that are associated with poor performance on cognitive tests that are dependent on function of the prefrontal cortex (PFC) and hippocampus (1, 2). Additionally, these SNPs have also been associated with variations in functional magnetic resonance imaging (fMRI) indexes of prefrontal cortical activity during working memory tasks (1, 3). Moreover, converging lines of evidence indicate that GRM3 represents a major locus associated with schizophrenia (1, 2, 4), bipolar disorder (5, 6), and substance abuse disorders (6-8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10-12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.Previous studies have revealed that pharmacological activation of group II mGlu receptors (mGlu 2 and mGlu 3 ) results in longterm depression (LTD) of excitatory transmission in layer V of the rat medial prefrontal cortex (mPFC) (13-16). Although it is not known whether induction of LTD in the mPFC is mediated by mGlu 2 or mGlu 3 , previous studies suggest that presynaptically localized mGlu 2 is typically responsible for inhibition of synaptic transmission by group II mGlu receptor agonists at other synapses (17-23). However, evidence suggests that induction of LTD in the mPFC is dependent upon activation of a postsynaptic group II mGlu receptor (15, 16), suggesting that this response is mechanistically distinct from presynaptic effects of group II mGlu receptor agonists on transmission at other synapses. Unfortunately, a lack of pharmacological agents that can selectively antagonize mGlu 3 or mGlu 2 has impaired progress in this area. To allow us to begin studies aimed at understanding the role of mGlu 3 in regulation of mPFC function, we developed a series of negative allosteric modulator...

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Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Activation of presynaptic GPCRs provides a powerful means to modulate information flow (20,21). It has historically been difficult to study neuromodulatory influences on long-range synaptic connectivity, and, to date, only a few studies have investigated GPCR modulation of presynaptic release from ChR2-expressing terminals (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of presynaptic G protein-coupled receptors (GPCRs) powerfully regulates information flow in neural circuits by modulating presynaptic release probability (20,21). Having established the functional network organization of the corticoraphe circuit, we next examined its potential regulation by neuromodulation, specifically asking whether PFC synapses onto 5-HT and GABA neurons were differentially modulated by GPCR activation.…”

Section: Feed-forward Inhibition Of Local Drn Gaba Interneurons By Opmentioning

confidence: 99%

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Geddes

Assadzada

Lemelin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Serotonin (5-HT) neurons located in the raphe nuclei modulate a wide range of behaviors by means of an expansive innervation pattern. In turn, the raphe receives a vast array of synaptic inputs, and a remaining challenge lies in understanding how these individual inputs are organized, processed, and modulated in this nucleus to contribute ultimately to the core coding features of 5-HT neurons. The details of the long-range, top-down control exerted by the medial prefrontal cortex (mPFC) in the dorsal raphe nucleus (DRN) are of particular interest, in part, because of its purported role in stress processing and mood regulation. Here, we found that the mPFC provides a direct monosynaptic, glutamatergic drive to both DRN 5-HT and GABA neurons and that this architecture was conducive to a robust feed-forward inhibition. Remarkably, activation of cannabinoid (CB) receptors differentially modulated the mPFC inputs onto these cell types in the DRN, in effect regulating the synaptic excitatory/inhibitory balance governing the excitability of 5-HT neurons. Thus, the CB system dynamically reconfigures the processing features of the DRN, a mood-related circuit believed to provide a concerted and distributed regulation of the excitability of large ensembles of brain networks.optogenetics | synapse | glutamate receptors | anxiety | depression T he phylogenetically old neurotransmitter serotonin (5-HT) is known to regulate a remarkably wide range of brain functions and behaviors, such as mood, aggression, reward, perception, levels of arousal, and decision making (1-5). The 5-HT-containing neurons are localized in a collection of small brainstem nuclei collectively known as the raphe nuclei, with the largest being the dorsal raphe nucleus (DRN). These neurons send extensive and widespread axonal projections throughout the forebrain (6). As such, the firing of a relatively small number of 5-HT neurons is powerfully poised to regulate the excitability of large ensembles of neural networks distributed across virtually the entire brain. However, little is known about how the synaptic networks impinging onto the DRN regulate the excitability of its constituent cells to generate the core feature selectivity of 5-HT neurons and, ultimately, to regulate the dynamic output of 5-HT to the brain. A significant step forward in this direction has recently been achieved by a number of anatomical studies that provide a comprehensive list of the brain regions projecting to the DRN, as well as detailed cartography of the connectivity patterns of these inputs to local cellular elements within the DRN subnetwork (i.e., 5-HT neurons, local GABAergic neurons) (7-9). The top-down control exerted by the phylogenetically recent medial prefrontal cortex (mPFC) over the DRN is of particular importance, in part, because of the purported role of this pathway in regulating several aspects of motivation and stress processing, and in mediating antidepressant-like effects (1, 10, 11). The mechanistic details of this long-range connectivity are elusive, howe...

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“…The loci meeting genome-wide significance in the largest genome-wide association study of schizophrenia ever conducted [8] include genes coding proteins shown to directly affect neuronal oscillations, such as MGluR3 ( δ , θ , and β ) [56, 57], GluR1 ( δ – γ interactions) [58], HCN ( θ and α ) [41, 42, 59], nAchR ( θ ) [60], T-type calcium channels ( δ ) [44], and Nr2Ar ( γ ) [61]. Further genome-wide associations concern genes that may be indirectly involved in rhythms, expressed in GABAergic interneurons, or regulate synaptic transmission or neurodevelopment [8, 9].…”

Section: Cellular Molecular and Circuit Level Changes Alter Rhythmsmentioning

confidence: 99%

Brain Rhythms Connect Impaired Inhibition to Altered Cognition in Schizophrenia

Pittman-Polletta

Kocsis

Vijayan

et al. 2015

Biological Psychiatry

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In recent years, schizophrenia research has focused on inhibitory interneuron dysfunction at the level of neurobiology, and on cognitive impairments at the psychological level. Reviewing both experimental and computational findings, we show how the temporal structure of the activity of neuronal populations, exemplified by brain rhythms, can begin to bridge these levels of complexity. Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia.

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

Cited by 33 publications

References 38 publications

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Brain Rhythms Connect Impaired Inhibition to Altered Cognition in Schizophrenia

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