Gene expression meta-analysis reveals the down-regulation of three GABA receptor subunits in the superior temporal gyrus of patients with schizophrenia

Frajman, Assaf; Maggio, Nicola; Muler, Inna; Haroutunian, Vahram; Katsel, Pavel; Yitzhaky, Assif; Weiser, Mark; Hertzberg, Libi

doi:10.1016/j.schres.2020.04.027

Cited by 15 publications

(9 citation statements)

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“…This study identified a different set of schizophrenia-associated genes which were not found in previous studies that utilized the complete hippocampus, including the calcium voltage-gated channel subunit alpha1C ( CACNA1C ) and the glutamate metabotropic receptor 3 ( GRM3 ). Further transcriptome studies of past years have proven that altered gene expression levels in different brain regions of schizophrenia patients underline the genetic aspect of this disease [ 89 , 90 , 91 , 92 , 93 , 94 ]. The most recent of these analyses could interestingly show an altered expression of the γ-aminobutyric acid-A (GABA-A) receptor-subunits GABRA1 , GABRA2 and GABRB3 in the dorsolateral prefrontal cortex and in the superior temporal gyrus [ 91 , 93 ].…”

Section: Genetic and Environmental Risk Factors Induce Hippocampal De...mentioning

confidence: 99%

“…Further transcriptome studies of past years have proven that altered gene expression levels in different brain regions of schizophrenia patients underline the genetic aspect of this disease [ 89 , 90 , 91 , 92 , 93 , 94 ]. The most recent of these analyses could interestingly show an altered expression of the γ-aminobutyric acid-A (GABA-A) receptor-subunits GABRA1 , GABRA2 and GABRB3 in the dorsolateral prefrontal cortex and in the superior temporal gyrus [ 91 , 93 ]. These observations may increase interest on the role of GABA-A receptor-subunits and their role in schizophrenia.…”

Section: Genetic and Environmental Risk Factors Induce Hippocampal De...mentioning

confidence: 99%

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Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Wegrzyn

Juckel

Faissner

2022

IJMS

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Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.

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Section: Genetic and Environmental Risk Factors Induce Hippocampal De...mentioning

confidence: 99%

Section: Genetic and Environmental Risk Factors Induce Hippocampal De...mentioning

confidence: 99%

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Wegrzyn

Juckel

Faissner

2022

IJMS

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“…Additionally, lower expression of GABRB3 protein has been reported in the superior frontal cortex [Brodmann Area 9 (BA9)] of patients with schizophrenia versus controls 19 . A systematic gene expression analysis of 22 GABA related genes in postmortem superior temporal gyrus (STG) samples of both elderly and young patients with schizophrenia showed a downregulation of Gabrb3 20 .…”

Section: Introductionmentioning

confidence: 99%

Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction

Agrud

Subburaju

Goel

et al. 2022

Sci Rep

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Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor β3 subunit endothelial cell conditional knockout (Gabrb3ECKO) mice, the β3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3ECKO telencephalon that persists in the adult neocortex. Gabrb3ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3ECKO mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3ECKO mice. The Gabrb3ECKO mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated ‘worm-like’ nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3ECKO mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.

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“…The explanation for this could be found in the distinction between OCD and obsessive-compulsive personality disorder (OCPD). For example, Jager et al (2020) found OCD and OCPD to be comorbid with misophonia, but at a different level: 2.8% of the patients had comorbidity with OCD, while 10.3389/fnins.2022.971752 26% had comorbid symptoms of OCPD. This former prevalence is only slightly higher than population prevalence for OCD (1.6%;den Braber et al, 2016), but the latter is a substantial increase for OCPD [7.8% in the US; (Grant et al, 2004)].…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, nearby TENM2 on chromosome 5 lie GABA receptor subunit genes (GABRG2, GABRB2, GABRA1), which could also be mediators of the effect as these are well-known genes expressed across the whole brain. GABA receptor genes have been associated with many other disorders ( Frajman et al, 2020 ), so that a mediating role of GABA remains a possibility where it could be hypothesized that functional excitation/inhibition ratios mediate the sensitivity to rage-related misophonia. On the other hand, these GABA receptor genes are mainly reported to be susceptibility genes for epilepsy ( Treiman, 2001 ; Cossette et al, 2002 ; ILAE Consortium, 2014 ; Riaz et al, 2021 ), where no significant association was found between misophonia and epilepsy, which would refute the mediating role for GABA.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study of a rage-related misophonia symptom and the genetic link with audiological traits, psychiatric disorders, and personality

et al. 2023

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IntroductionPeople with misophonia experience strong negative emotional responses to sounds and associated stimuli—mostly human produced—to an extent that it may cause impairment in social functioning. The exact nature of the disorder remains a matter of ongoing research and debate. Here, we investigated the genetic etiology of misophonia to understand contributing genetic factors and shed light on individual differences in characteristics that are related to the disorder.MethodsFor misophonia, we used an unpublished genome-wide association study (GWAS) from genetic service provider 23andMe, Inc., on a self-report item probing a single common misophonic symptom: the occurrence of rage when others produce eating sounds. First, we used gene-based and functional annotation analyses to explore neurobiological determinants of the rage-related misophonia symptom. Next, we calculated genetic correlations (rG) of this rage-related misophonia symptom GWAS with a wide range of traits and disorders from audiology (tinnitus, hearing performance, and hearing trauma), psychiatry, neurology, and personality traits.ResultsThe rage-related misophonia symptom was significantly correlated with tinnitus, major depression disorder (MDD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD; 0.12 < rG < 0.22). Stronger genetic correlations (0.21 < rG < 0.42) were observed for two clusters of personality traits: a guilt/neuroticism and an irritability/sensitivity cluster. Our results showed no genetic correlation with attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and psychotic disorders. A negative correlation with autism spectrum disorder (ASD) was found, which may be surprising given the previously reported comorbidities and the sensory sensitivity reported in ASD. Clustering algorithms showed that rage-related misophonia consistently clustered with MDD, generalized anxiety, PTSD, and related personality traits.DiscussionWe conclude that—based on the genetics of a common misophonia symptom—misophonia most strongly clusters with psychiatric disorders and a personality profile consistent with anxiety and PTSD.

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Gene expression meta-analysis reveals the down-regulation of three GABA receptor subunits in the superior temporal gyrus of patients with schizophrenia

Cited by 15 publications

References 71 publications

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction

A genome-wide association study of a rage-related misophonia symptom and the genetic link with audiological traits, psychiatric disorders, and personality

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