Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder

Kandaswamy, Radhika; McQuillin, Andrew; Sharp, Sally I.; Fiorentino, Alessia; Anjorin, Adebayo; Blizard, Robert; Curtis, David; Gurling, Hugh

doi:10.1001/jamapsychiatry.2013.38

Cited by 32 publications

(20 citation statements)

References 53 publications

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“…Grm3 has previously been shown to be expressed in human astrocytes and glioma cells [5]. In addition, the GRM3 gene has been found to be associated with bipolar affective disorder [19] and several recent studies have shown that mutations in Grm3 are positively associated with melanoma and other tumors [22,31,40,55]. Here we found that Grm3 mainly expressed in B cells (Fig.…”

Section: Discussionsupporting

confidence: 69%

Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

Liu

Chen³

et al. 2015

Clinical Immunology

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Section: Discussionsupporting

confidence: 69%

Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

Liu

Chen³

et al. 2015

Clinical Immunology

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“…Thus, it is impossible to directly estimate the level of receptor occupancy achieved in the CNS with the doses used. However, it is also possible that in vivo efficacy requires high mGlu 3 receptor occupancy, a property that has been reported for mGlu 1 and mGlu 5 NAMs (33,34). In contrast, mGlu receptor positive allosteric modulators (PAMs) can produce full efficacy with relatively low occupancy in the CNS because of the contributions of both affinity and cooperativity to PAM potency at a receptor (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…Recording aCSF was identical aside from the exclusion of sodium ascorbate and N-acetylcystine. fEPSPs were recorded from layer V of PL, using a pulled-glass pipette (3)(4)(5), and evoked by electrical stimulation of layer II/III (0.05 Hz), using a concentric bipolar electrode. Three consecutive fEPSP slopes were averaged and then normalized to the mean baseline slope before drug application.…”

Section: Methodsmentioning

confidence: 99%

“…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)(7)(8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10)(11)(12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.…”

mentioning

confidence: 99%

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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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“…This protein is involved in learning, memory, anxiety and the perception of pain. 35 The obesity with hyperinsulinism in patient 2 is very likely to be caused by deletion of the CD36 gene (Figure 2). This gene encodes a glycoprotein of the platelet surface and may function in the transport and/or as a regulator of fatty acid transport.…”

Section: Discussionmentioning

confidence: 99%

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

et al. 2014

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Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the alpha 2 delta subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene

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Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder

Cited by 32 publications

References 53 publications

Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

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

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

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