Cingulate Cortex In Schizophrenia Research Articles

Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels.

Background:Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia.Methods:This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels.Results:We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose.Limitations:Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study.Conclusion:This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

T240. Relationship Between Cognitive Performance and Superficial White Matter Integrity in the Cingulate Cortex in Schizophrenia: A DWI Study Using a Novel Atlas

Evidence is mounting to suggest that changes in superficial white matter (SWM) U-shaped short-range fibers are integral components of schizophrenia neuropathology, a theory that is supported by findings from postmortem studies and less often in vivo in patients with SZ. This diffusion weighted imaging (DWI) study aimed to investigate SWM in people with SZ and to determine its relationship with cognition.

Disrupted relationship between “resting state” connectivity and task-evoked activity during social perception in schizophrenia

Schizophrenia has been described as a self-disorder, whereas social deficits are key features of the illness. Changes in “resting state” activity of brain networks involved in self-related processing have been consistently reported in schizophrenia, but their meaning for social perception deficits remains poorly understood. Here, we applied a novel approach investigating the relationship between task-evoked neural activity during social perception and functional organization of self-related brain networks during a “resting state”.“Resting state” functional MRI was combined with task-related functional MRI using a social perception experiment. Twenty-one healthy control participants (HC) and 21 out-patients with a diagnosis of schizophrenia (SCH) were included. There were no significant differences concerning age, IQ, education and gender between the groups.Results showed reduced “resting state” functional connectivity between ventromedial prefrontal cortex and dorsal posterior cingulate cortex in SCH, compared to HC. During social perception, neural activity in dorsal posterior cingulate cortex and behavioral data indicated impaired congruence coding of social stimuli in SCH. Task-evoked activity during social perception in dorsal posterior cingulate cortex co-varied with dorsal posterior cingulate cortex-ventromedial prefrontal cortex functional connectivity during a “resting state” in HC, but not in SCH. Task-evoked activity also correlated with negative symptoms in SCH.These preliminary findings, showing disrupted prediction of social perception measures by “resting state” functioning of self-related brain networks in schizophrenia, provide important insight in the hypothesized link between self and social deficits. They also shed light on the meaning of “resting state” changes for tasks such as social perception.

Small non-coding RNA expression from anterior cingulate cortex in schizophrenia shows sex specific regulation

MicroRNAs (miRNAs) are known to regulate the expression of genes that are important for brain development and function, but the roles of other classes of small non-coding RNAs (sncRNAs) are less well understood. Additionally, although miRNA expression studies have been conducted in post-mortem brain samples from schizophrenia (SCZ) patients, other classes of sncRNAs are yet to be investigated in SCZ. We profiled the expression of miRNAs, piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) in SCZ by applying small RNA sequencing (RNA-Seq) to sncRNA isolated from post-mortem anterior cingulate cortex (ACC) of SCZ-affected individuals (n=22) and matched controls (n=22). We identified about one-third of annotated miRNAs, one-quarter of snoRNAs and a small proportion of piRNAs and snRNAs. No sncRNAs were significantly differentially expressed between SCZ and controls, but there was evidence for an interaction between disease status and sex on the expression level of a number of miRNAs and snoRNAs. Many of these transcripts exhibited differential expression between male and female cases, and/or between female cases and controls, suggesting sex based dysregulation in ACC of SCZ. These findings require replication in an independent sample, but our study provides further insights into the potential involvement of sncRNAs in brain function and SCZ.

Sex differences in GABAergic gene expression occur in the anterior cingulate cortex in schizophrenia

GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication.

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

BackgroundCurrent pharmacological treatments for schizophrenia target G protein-coupled receptors (GPCRs), including dopamine receptors. Ligand-bound GPCRs are regulated by a family of G protein-coupled receptor kinases (GRKs), members of which uncouple the receptor from heterotrimeric G proteins, desensitize the receptor, and induce receptor internalization via the arrestin family of scaffolding and signaling molecules. GRKs initiate the activation of downstream signaling pathways, can regulate receptors and signaling molecules independent of GPCR phosphorylation, and modulate epigenetic regulators like histone deacetylases (HDACs). We hypothesize that the expression of GRK proteins is altered in schizophrenia, consistent with previous findings of alterations upstream and downstream from this family of molecules that facilitate intracellular signaling processes. MethodsIn this study, we measured protein expression via Western blot analysis for GRKs 2, 3, 5, and 6 in the anterior cingulate cortex of patients with schizophrenia (n=36) and a comparison group (n=33). To control for antipsychotic treatment, we measured these same targets in haloperidol-treated vs. untreated rats (n=10 for both). ResultsWe found increased levels of GRK5 in schizophrenia. No changes were detected in GRK protein expression in rats treated with haloperidol decanoate for 9months. ConclusionThese data suggest that increased GRK5 expression may contribute to the pathophysiology of schizophrenia via abnormal regulation of the cytoskeleton, endocytosis, signaling, GPCRs, and histone modification.

Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

The anterior cingulate cortex (ACC) is one of several brain regions that are abnormal in schizophrenia (SZ). Here we compared markers of synapse and mitochondrial function using western blots of postmortem ACC in: 1) normal controls (NCs, n=13) vs subjects with SZ (n=25); NC, treatment-resistant SZ, and treatment-responsive SZ; and 3) NC and SZ treated with typical or atypical antipsychotic drugs (APDs). Protein levels of synaptophysin, mitofusin-2, vGLUT1, and calcineurin did not differ between the NC and SZ group as a whole, or the NCs vs the SZ group divided by treatment response or type of APDs. In several cases, the levels of vGLUT1 were minuscule or absent. The proportion of NCs lacking vGLUT1 was significantly less than that of the SZ groups. There were several positive correlations across all subjects between: 1) synaptophysin and vGLUT1; 2) synaptophysin and calcineurin; 3) synaptophysin and mitofusin; and 4) calcineurin and mitofusin. Synaptophysin and calcineurin were positively correlated in responders, and this correlation was significantly stronger than that in treatment-resistant SZ subjects or in NCs. Synaptophysin and calcineurin were positively correlated in SZ patients on atypical APDs; this correlation was significantly stronger than that in SZ patients on typical APDs or in NCs. Mitofusin-2 and calcineurin were positively correlated in SZ patients on atypical APDs and in NCs; this correlation was stronger in SZ patients on atypical rather than typical APDs or in NCs. The correlation between these proteins, which have roles in synaptic vesicle cycling, glutamate transmission, mitochondrial fusion, and calcium buffering, is complex and was differentially regulated among the groups.

Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities

The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data, however, are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. We investigated the dorsal anterior cingulate cortex (dACC) in 13 men with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neurone and glial numbers, and glia/neurone index (GNI) in both layers II-III and V-VI. We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neurone numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development. Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post mortem histopathological studies and in vivo brain imaging findings in patients.

Nicotine effects on anterior cingulate cortex in schizophrenia and healthy smokers as revealed by EEG-informed fMRI

Nicotine can have beneficial effects on attention performance and corresponding brain function in both schizophrenia patients and healthy controls, but it remains controversial whether nicotine affects brain function differentially in patients vs. controls. The effects of nicotine on brain activity elicited by attention-requiring oddball-type tasks have not been studied in schizophrenia patients. In this study we sought to investigate the impact of nicotine on the p300 evoked potential component and corresponding fMRI (functional magnetic resonance imaging) activation measures in schizophrenia patients and controls. Applying a double-blind, placebo-controlled cross-over design, the effects of 1mg nasal nicotine on brain activity elicited by a visual oddball-type task in N=14 schizophrenia and N=15 control smokers were studied with simultaneous EEG-fMRI. EEG single trial amplitudes were used to inform the fMRI analysis. We found a nicotine-associated increase in P300-informed fMRI activation in schizophrenia patients and controls, mainly in the anterior cingulate and adjacent medial frontal cortex. No group differences in the response to nicotine were found. Remarkably, averaged EEG and fMRI activation measures considered in isolation were largely unaffected by nicotine. Taken together, the effects of nicotine on P300 amplitude-associated brain activation do not seem to be fundamentally different in schizophrenic smokers and healthy controls.

Functional and Anatomical Connectivity Abnormalities in Cognitive Division of Anterior Cingulate Cortex in Schizophrenia

IntroductionCurrent pathophysiological theories of schizophrenia highlight the role of altered brain functional and anatomical connectivity. The cognitive division of anterior cingulate cortex (ACC-cd) is a commonly reported abnormal brain region in schizophrenia for its importance in cognitive control process. The aim of this study was to investigate the functional and anatomical connectivity of ACC-cd and its cognitive and clinical manifestation significance in schizophrenia by using the resting-state functional magnetic resonance imaging (fMRI) and the diffusion tensor imaging (DTI).MethodsThirty-three medicated schizophrenics and 30 well-matched health controls were recruited. Region-of-interest (ROI)-based resting-state functional connectivity analysis and Tract-Based Spatial Statistics (TBSS) were performed on 30 patients and 30 controls, and 24 patients and 29 controls, respectively. The Pearson correlation was performed between the imaging measures and the Stroop performance and scores of the Positive and Negative Syndrome Scale (PANSS), respectively.ResultsPatients with schizophrenia showed significantly abnormal in the functional connectivity and its hemispheric asymmetry of the ACC-cd with multiple brain areas, e.g., decreased positive connectivity with the bilateral putamen and caudate, increased negative connectivity with the left posterior cingulated cortex (PCC), increased asymmetry of connectivity strength with the contralateral inferior frontal gyrus (IFG). The FA of the right anterior cingulum was significantly decreased in patients group (p = 0.014). The abnormal functional and structural connectivity of ACC-cd were correlated with Stroop performance and the severity of the symptoms in patients.ConclusionsOur results suggested that the abnormal connectivity of the ACC-cd might play a role in the cognitive impairment and clinical symptoms in schizophrenia.

Disrupted white matter connectivity is associated with reduced cortical thickness in the cingulate cortex in schizophrenia

IntroductionBoth impaired white matter connectivity and alterations in gray matter morphometry have repeatedly been reported in schizophrenia. Neurodevelopmental models propose a close linkage between gray matter alterations and white matter deficits. However, there are no studies investigating alterations in cortical thickness in relation to white matter connectivity changes. MethodsThis combined diffusion tensor imaging (DTI) – surface based morphometry study examined a potential linkage between disruption in white matter connectivity and alterations in cortical thickness. Cortical thickness was analyzed using the FreeSurfer software package (version 4.0.5, http://surfer.nmr.harvard.edu) in a sample of 19 patients with schizophrenia and 20 healthy controls. ResultsWhole brain node-by-node correlational analysis revealed a highly significant association (r=−.8, p<.0001) between disturbed white matter connectivity in the superior temporal cortex and diminished cortical thickness in the posterior part of the cingulate cortex (Brodmann area 23/31). ConclusionsThis result indicates a significant linkage between disturbed white matter connectivity and reduced cortical thickness in a relevant node of the default mode network that is held to be of high pathophysiological relevance in schizophrenia. The result moreover provides support for the assumption of a neurodevelopmental pathogenesis of the disorder.

The subgenual cingulate gyrus exhibits lower rates of bifurcation in schizophrenia than in controls, bipolar disorder and depression

The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.

Cingulate Cortex in Schizophrenia: its relation with negative symptoms and psychotic onset. A review study.

Cingulate Cortex in Schizophrenia: its relation with negative symptoms and psychotic onset. A review study.

Anterior Cingulate Cortex: Unique Role in Cognition and Emotion

Anterior Cingulate Cortex: Unique Role in Cognition and Emotion

Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia

Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.

Cingulate White Matter Neurons in Schizophrenia and Bipolar Disorder

Increased neuronal density in prefrontal, parietal, and temporal white matter of schizophrenia subjects is thought to reflect disordered neurodevelopment; however, it is not known if this cellular alteration affects the cingulate cortex and whether similar changes exist in bipolar disorder. Eighty-two postmortem specimens (bipolar 15, schizophrenia 22, control 45) were included in this clinical study. Densities for two neuronal markers, neuron-specific nuclear protein (NeuN) and neuregulin 1 alpha (NRG), were determined in white matter up to 2.5 mm beneath the anterior cingulate cortex; density of NeuN immunopositive neurons (NeuN+) was also determined for a subset of cases in prefrontal cortex. Changes during normal development were monitored in a separate cohort of 14 brains. Both the schizophrenia and bipolar cohorts demonstrated a twofold increase in NeuN+ density in cingulate white matter; this effect could be attributed to approximately 25% of cases that exceeded the second standard deviation from control subjects. Similar changes were observed in prefrontal cortex. In contrast density of NRG expressing neurons was unaltered. Cases with increased NeuN+ densities in two-dimensional (2-D) counts also showed a pronounced, > fivefold elevation in NeuN+ nuclei per cubic millimeter. Additionally, the developmental cohort demonstrated a 75% decline in NeuN+ neuronal density during the first postnatal year but was stable thereafter. Increased neuronal density in white matter of cingulate cortex in schizophrenia provides further evidence that this alteration occurs in multiple cortical areas. Similar changes in some cases with bipolar illness suggest that the two disorders may share a common underlying defect in late prenatal or early postnatal neurodevelopment.

N-Methyl-D-Aspartate Receptor and Calbindin-Containing Neurons in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder

Glutamatergic modulation of gamma-aminobutyric acid (GABA) interneurons via the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor in the cerebral cortex contributes to the pathophysiology of schizophrenia and bipolar disorder. Previously, we found that, in the anterior cingulate cortex (ACCx), the number of GABA cells that expressed the messenger RNA (mRNA) for the NMDA NR2A subunit was significantly decreased in subjects with schizophrenia and bipolar disorder and that this decrease occurred most prominently in layer 2. In this study, we hypothesized that the subset of GABA interneurons that contained the calcium-binding protein calbindin (CB), by virtue of their preferential localization to layer 2, might be particularly affected. We simultaneously labeled the mRNA for the NMDA NR2A subunit with [(35)S] and the mRNA for CB with digoxigenin with an immunoperoxidase procedure. We found that, in the normal human ACCx, only approximately 10% of all CB-containing cells expressed NR2A mRNA. However, compared with the normal control subjects and subjects with bipolar disorder, the density of CB+/NR2A+ neurons in layer 2 was increased by 41% to 44 % in subjects with schizophrenia, whereas the amount of NR2A mRNA/CB+ neurons was unchanged. These observations suggest that, in schizophrenia, a number of CB-containing cells that normally do not express NR2A might become NR2A-expressing or, perhaps not mutually exclusively, the number of CB-expressing cells might be increased and these cells express NR2A. The findings of this study highlight the notion that glutamatergic innervation of subsets of GABA cells might be differentially altered in schizophrenia and bipolar disorder.

Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

Altered expression of structural and functional molecules expressed by astrocytes may play a role in the pathophysiology of schizophrenia. We investigated the hypothesis that the astrocytic enzyme glutamine synthetase, involved in maintaining the glutamate–glutamine cycle, and the cytoskeletal molecule glial fibrillary acidic protein (GFAP) are abnormally expressed in schizophrenia. We used Western blot analysis to measure levels of glutamine synthetase and GFAP in several brain regions of subjects with schizophrenia and a comparison group. We found that glutamine synthetase protein expression was significantly decreased in the superior temporal gyrus, and both glutamine synthetase and GFAP were significantly reduced in the anterior cingulate cortex in schizophrenia. Neither molecule demonstrated altered expression in the dorsolateral prefrontal cortex, primary visual cortex, or hippocampus. Chronic treatment with haloperidol did not alter the expression of these molecules in the rat brain, suggesting that our findings are not due to a medication effect. These data support an astrocytic component to the pathophysiology of schizophrenia and suggest that astrocytic molecules involved in enzymatic activity and cytoskeletal integrity may have a role in disease-related abnormalities in this illness.

Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology

The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder

The aim of this study was to examine whether glutamatergic inputs onto GABA interneurons via the kainate receptor in the anterior cingulate cortex may be altered in schizophrenia and bipolar disorder. Hence, in a cohort of 60 post-mortem human brains from schizophrenia, bipolar disorder, and normal control subjects, we simultaneously labeled the mRNA for the GluR5 or GluR6 subunit of the kainate receptor with [ 35S] and the mRNA for the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) 67 with digoxigenin using an immunoperoxidase method. The density of the GAD 67 mRNA-containing neurons that co-expressed GluR5 mRNA was decreased by 43% and 40% in layer 2 of the anterior cingulate cortex in schizophrenia and bipolar disorder, respectively. In contrast, the density of the GAD 67 mRNA-containing cells that expressed GluR6 mRNA was unaltered in either condition. Furthermore, the amount of GluR5 or GluR6 mRNA in the GAD 67 mRNA-expressing cells that contained a detectable level of these transcripts was also unchanged. Finally, the density of cells that did not contain GAD 67 mRNA, which presumably included all pyramidal neurons, but expressed the mRNA for the GluR5 or GluR6 subunit was not altered. Thus, glutamatergic modulation of inhibitory interneurons, but not pyramidal neurons, via kainate receptors containing the GluR5 subunit appears to be selectively altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.