Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive–compulsive disorder

Arnold, Paul; MacMaster, Frank P.; Richter, Margaret A.; Hanna, Gregory L.; Sicard, Tricia; Burroughs, Eliza; Mirza, Yousha; Easter, Phillip C.; Rose, Michelle; Kennedy, James L.; Rosenberg, David

doi:10.1016/j.pscychresns.2009.02.005

Cited by 83 publications

(58 citation statements)

References 27 publications

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“…Therefore, metabolic changes due to stress and anticipatory anxiety cannot be fully excluded. Finally, the present study did not control for the genetic background, eg, variation in the NMDA 2B receptor gene (GRIN2B), which has been shown to influence ACC Glx concentration (Arnold et al, 2009). Also, smoking or smoking cessation impacting anterior cingulate proton spectroscopy glutamate levels were not considered as potentially confounding factors (Mashhoon et al, 2011).…”

Section: Discussionmentioning

confidence: 95%

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Zwanzger

Zavorotnyy

Gencheva

et al. 2013

Neuropsychopharmacol

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According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate þ glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17) ¼ 149.41; po0.0001; PSS: F(1,17) ¼ 88.03; po0.0001) and heart rate (HR: F(1,17) ¼ 72.79; po0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17) ¼ 15.94; p ¼ 0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11) ¼ 8.68; p ¼ 0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both API max (r ¼ 0.598; p ¼ 0.009) and maximum heart rate (HR max ) during challenge (r ¼ 0.519; p ¼ 0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

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Section: Discussionmentioning

confidence: 95%

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Zwanzger

Zavorotnyy

Gencheva

et al. 2013

Neuropsychopharmacol

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“…The interest in using imaging phenotypes for genetic studies is rapidly growing. For example, association was identified between a polymorphism of the ionotropic, N-methyl-D-aspartate 2B (GRIN2B) glutamate receptor and decreased glutamate (Glx) in the ACC, a region consistently implicated in OCD (Arnold et al, 2009).…”

Section: Integrating Anatomical and Neurochemical Modelsmentioning

confidence: 99%

Invasive Circuitry-Based Neurotherapeutics: Stereotactic Ablation and Deep Brain Stimulation for OCD

Greenberg

Rauch

Haber

2009

Neuropsychopharmacol

310

229

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Psychiatric neurosurgery, specifically stereotactic ablation, has continued since the 1940s, mainly at a few centers in Europe and the US. Since the late 1990s, the resurgence of interest in this field has been remarkable; reports of both lesion procedures and the newer technique of deep brain stimulation (DBS) have increased rapidly. In early 2009, the US FDA granted limited humanitarian approval for DBS for otherwise intractable obsessive-compulsive disorder (OCD), the first such approval for a psychiatric illness. Several factors explain the emergence of DBS and continued small-scale use of refined lesion procedures. DBS and stereotactic ablation have been successful and widely used for movement disorders. There remains an unmet clinical need: current drug and behavioral treatments offer limited benefit to some seriously ill people. Understandings of the neurocircuitry underlying psychopathology and the response to treatment, while still works in progress, are much enhanced. Here, we review modern lesion procedures and DBS for OCD in the context of neurocircuitry. A key issue is that clinical benefit can be obtained after surgeries targeting different brain structures. This fits well with anatomical models, in which circuits connecting orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), basal ganglia, and thalamus are central to OCD pathophysiology and treatment response. As in movement disorders, dedicated interdisciplinary teams, here led by psychiatrists, are required to implement these procedures and maintain care for patients so treated. Available data, although limited, support the promise of stereotactic ablation or DBS in carefully selected patients. Benefit in such cases appears not to be confined to obsessions and compulsions, but includes changes in affective state. Caution is imperative, and key issues in long-term management of psychiatric neurosurgery patients deserve focused attention. DBS and contemporary ablation also present different patterns of potential benefits and burdens. Translational research to elucidate how targeting specific nodes in putative OCD circuitry might lead to therapeutic gains is accelerating in tandem with clinical use.

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“…The same authors also described a significant association between anterior cingulate glutamatergic concentration and the GRIN2B rs1019385 polymorphism. 49 The particular implication of ventromedial regions in the development of contamination/ cleaning symptoms may explain the specific contribution of GRIN2B to the genetic susceptibility to this symptom dimension.…”

mentioning

confidence: 99%

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Alonso

Gratacòs

Segalás

et al. 2012

jpn

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Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B. Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.

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Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive–compulsive disorder

Cited by 83 publications

References 27 publications

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Invasive Circuitry-Based Neurotherapeutics: Stereotactic Ablation and Deep Brain Stimulation for OCD

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

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