Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

Kirschstein, Timo; Bauer, M R; Müller, Luisa; Rüschenschmidt, Christiane; Reitze, Margit; Becker, Albert; Schoch, Susanne; Beck, Hanno

doi:10.1523/jneurosci.4572-06.2007

Cited by 56 publications

(50 citation statements)

References 57 publications

(78 reference statements)

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“…30 The mGluR1 and mGluR5 dimers presented as 2 bands (270-280 kDa; quantified together as the dimer), whereas the monomer presented as a single band (150 kDa). We and others have previously reported this pattern of bands for group 1 mGluRs, 29,31,32 including the use of alternate mGluR1 and mGluR5 antibodies, and specificity has been confirmed using respective KO mice. 32,33 The mGluR1 dimeric and monomeric bands appeared at similar intensities.…”

Section: Resultssupporting

confidence: 72%

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

Lum

Millard

Huang

et al. 2018

jpn

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IntroductionThe nucleus accumbens (NAcc), a major component of the ventral striatum, is believed to play a large role in the pathology of schizophrenia; however, there has been little direct investigation of this region in individuals with schizophrenia. Current antipsychotics are thought to target the NAcc and reduce a striatal hyperdopaminergic state, which was implicated in schizophrenia by early imaging and pharmacological studies.1,2 However, recent and further advanced imaging studies capable of analyzing the subregions of the striatum suggested the NAcc may not show a hyperdopaminergic state as much as neighbouring striatal regions. 3,4 In agreement with this idea, a recent postmortem study reported unaltered protein levels of the rate-limiting dopamine synthesis enzyme tyrosine hydroxylase within the NAcc.5 However, protein expression of the vesicle glutamate transporter VGLUT2 was found to be increased, suggesting altered glutamatergic signalling within the NAcc. 6 In support of this finding, increased asymmetric synapses, representative of glutamatergic projections, have been observed within the core of the NAcc in individuals with schizophrenia.7 Furthermore, these synapses were observed to have reduced postsynaptic density area. Taken together, these recent studies suggest that altered glutamatergic neurotransmission to the NAcc is associated with schizophrenia pathology; however, further evidence characterizing the glutamatergic system within the NAcc in individuals with schizophrenia is required.The NAcc receives dense excitatory input from the thalamus, hippocampus, prefrontal cortex (PFC) and amygdala, regions strongly associated with glutamatergic alterations in schizophrenia pathology. Background:The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic altera tions in the NAcc of a large schizophrenia cohort. Methods: We performed immunoblots on postmortem NAcc samples from 30 individ uals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the Nmethyldaspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Results: Protein levels of glutamatergic re ceptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Further more, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions be tween these receptors in this brain region. Limitations: Investigation of these proteins in antipsychoticnaive individuals, in addition to the subregions of the NAcc an...

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Section: Resultssupporting

confidence: 72%

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

Lum

Millard

Huang

et al. 2018

jpn

View full text Add to dashboard Cite

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“…This striking colocalization suggests that mGluR5 and DGL-␣ is involved in the molecular cascade, which detects surplus excitatory activity and induces 2-AG release to attenuate further glutamate release and the escalation of excitotoxicity. Importantly, both mGluR5 and long Homer isoforms are robustly downregulated after status epilepticus (Kirschstein et al, 2007). Moreover, elimination of other upstream components in 2-AG's biosynthetic route such as G q /G 11 G-proteins or PLC␤ 1 and its target CB 1 also led to increased seizure susceptibility (Kim et al, 1997;Marsicano et al, 2003;Wettschureck et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the CB₁Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus

Ludányi¹,

Erőss²,

Czirják³

et al. 2008

J. Neurosci.

217

176

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Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB 1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-␣, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ϳ60%, whereas its related ␤ isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB 1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB 1 -positive GABAergic boutons, but uncovered robust reduction in the fraction of CB 1 -positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB 1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

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“…Experimental epilepsy research has uncovered a complex relationship between synaptic plasticity and in vitro and in vivo models of seizures and epilepsy (Staley and Dudek, 2006;Kirschstein et al, 2007;Hellier et al, 2009), with the unifying hypothesis that intervening at the initial insult or onset of epileptogenesis is the most promising approach to treat the disease. Although our current work represents the first examination of therapeutic O-GlcNAcylation using in vitro and in vivo seizure models, others have shown therapeutic effects in multiple models of Alzheimer's disease (Borghgraef et al, 2013;Yuzwa et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus

Stewart¹,

Khan²,

Wang³

et al. 2017

J. Neurosci.

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O-GlcNAcylation is a ubiquitous and dynamic post-translational modification involving the O-linkage of ␤-N-acetylglucosamine to serine/threonine residues of membrane, cytosolic, and nuclear proteins. This modification is similar to phosphorylation and regarded as a key regulator of cell survival and homeostasis. Previous studies have shown that phosphorylation of serine residues on synaptic proteins is a major regulator of synaptic strength and long-term plasticity, suggesting that O-GlcNAcylation of synaptic proteins is likely as important as phosphorylation; however, few studies have investigated its role in synaptic efficacy. We recently demonstrated that acutely increasing O-GlcNAcylation induces a novel form of LTD at CA3-CA1 synapses, O-GlcNAc LTD. Here, using hippocampal slices from young adult male rats and mice, we report that epileptiform activity at CA3-CA1 synapses, generated by GABA A R inhibition, is significantly attenuated when protein O-GlcNAcylation is pharmacologically increased. This dampening effect is lost in slices from GluA2 KO mice, indicating a requirement of GluA2-containing AMPARs, similar to expression of O-GlcNAc LTD. Furthermore, we find that increasing O-GlcNAcylation decreases spontaneous CA3 pyramidal cell activity under basal and hyperexcitable conditions. This dampening effect was also observed on cortical hyperexcitability during in vivo EEG recordings in awake mice where the effects of the proconvulsant pentylenetetrazole are attenuated by acutely increasing O-GlcNAcylation. Collectively, these data demonstrate that the post-translational modification, O-GlcNAcylation, is a novel mechanism by which neuronal and synaptic excitability can be regulated, and suggest the possibility that increasing O-GlcNAcylation could be a novel therapeutic target to treat seizure disorders and epilepsy.

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Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

Cited by 56 publications

References 57 publications

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

Downregulation of the CB₁Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus

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Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

Cited by 56 publications

References 57 publications

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

Downregulation of the CB1Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus

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Downregulation of the CB₁Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus