Altered Dimerization of Metabotropic Glutamate Receptor 3 in Schizophrenia

Corti, Corrado; Crepaldi, Luca; Mion, Silvia; Roth, Adelheid; Xuereb, John H.; Ferraguti, Francesco

doi:10.1016/j.biopsych.2006.12.005

Cited by 73 publications

(60 citation statements)

References 53 publications

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“…This present study is the first to use RNA interference to target the expression of VGLUT1 in a specific brain region in vivo as a novel means of manipulating synaptic glutamate release. Hippocampal expression of VGLUT1 mRNA and protein is decreased in schizophrenia (Eastwood and Harrison, 2005;Sawada et al, 2005;Piyabhan and Reynolds, 2006) and, although striatal deficits have also been reported (Piyabhan and Reynolds, 2006;Nudmamud-Thanoi et al, 2007), cortical changes (which do occur in depression; Gilabert-Juan et al, 2012) are far less robust in schizophrenia (Corti et al, 2007;OniOrisan et al, 2008;Uezato et al, 2009;Eastwood and Harrison, 2010) and appear restricted to specific layers of the prefrontal cortex (Eastwood and Harrison, 2005;Bitanihirwe et al, 2009), whereas the amygdala remains unaffected . The principal finding of the current study is that administration of a VGLUT1-targeting lentiviral shRNA vector into the dorsal hippocampus of Targeting whole-brain VGLUT1 expression using conventional gene knockout strategies results in a 35-41% decrease in transporter levels in heterozygous animals (Tordera et al, 2007;Garcia-Garcia et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

King

Kurian

Qin

et al. 2013

Neuropsychopharmacol

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Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

King

Kurian

Qin

et al. 2013

Neuropsychopharmacol

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“…However, it is still possible that such alterations occur in a genetically predisposed subset of affected individuals, or that protein levels are altered in the absence of consistent changes in mRNA or that GRM3 receptors are altered in other ways. For example, Corti et al (2007) found a marked decrease in dimeric forms of GRM3 in the prefrontal cortex in schizophrenia, with no change in total GRM3. It is also possible that changes are region or layer specific.…”

Section: Effect Of Diagnosis On Expression Of Grm3 Transcriptsmentioning

confidence: 97%

“…We observed that in the CBDB/NIMH DLPFC collection, presence of the minor frequency 'T' allele predicted B20% higher relative expression of GRM3D4. If indeed this SNP predicts increased levels of truncated protein, which may retain the ability to dimerize with the full-length GRM3 receptor, this may affect dimerization and function of GRM3 in schizophrenia, as suggested by a recent study (Corti et al, 2007). We attempted to replicate this in the Stanley brain collection, but the minor allele was of even lower frequency in that collection, and the result was equivocal.…”

Section: Effects Of Snps On Grm3 Transcript Expressionmentioning

confidence: 98%

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

Sartorius

Weinberger

Hyde

et al. 2008

Neuropsychopharmacol

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Genetic variation in the metabotropic glutamate receptor 3 (GRM3, mGluR3) has been associated with schizophrenia, but the mechanism by which it confers risk is unknown. Previously, we reported the existence of a splice variant, GRM3D4, which has an exon 4 deletion and encodes a truncated form of the receptor that is expressed in brain. The aim of the present study was to determine whether expression of this splice variant is altered in individuals with schizophrenia and is affected by a risk genotype. We measured GRM3 and GRM3D4 transcripts in human dorsolateral prefrontal cortex (DLPFC) and hippocampus of the CBDB/NIMH collection (B70 controls, B30 schizophrenia patients) and in the DLPFC of the Stanley Array Collection. Expression data of GRM3 mRNA in the DLPFC were inconsistent: GRM3 was increased in schizophrenia patients in the CBDB/NIMH collection, but not in the Stanley Array Collection. GRM3 expression did not change in the frontal cortex of rats treated chronically with haloperidol or clozapine. An exon 3 SNP previously associated with schizophrenia (rs2228595) predicted increased expression of the GRM3D4 splice variant. Our results suggest that rs2228595, or a neighboring SNP in linkage disequilibrium with it, may contribute to risk for schizophrenia by modulating GRM3 splicing.

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“…In patients with schizophrenia, there is down-regulation of mGluR2 (22) and alterations in mGluR3 (23). Moreover, recent clinical trials showed positive results for mGluRII agonists in reducing symptoms in schizophrenia (24).…”

mentioning

confidence: 99%

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

Ster

Mateos²,

Grewe³

et al. 2011

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

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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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Altered Dimerization of Metabotropic Glutamate Receptor 3 in Schizophrenia

Cited by 73 publications

References 53 publications

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

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

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