Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human

Peng, Shi-Xiao; Pei, Jingwen; Rinaldi, Berardo; Jiang, Chen; Ge, Yu-Han; Jia, Min; Wang, Jun; Delahaye‐Duriez, Andrée; Sun, Jiahui; Zang, Yang; Shi, Yong-Yun; Zhang, Ning; Gao, Xiang; Milani, Donatella; Xu, Xiao; Sheng, Nengyin; Gérard, Bénédicte; Zhang, Chen; Bayat, Allan; Yang, Jianjun; Shi, Yun

doi:10.1038/s41380-022-01659-8

Cited by 14 publications

(7 citation statements)

References 51 publications

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“…Morphological analysis of neuronal cells in these models has reported reduced axonal and dendritic complexity and abnormal spine morphology in Setd1a heterozygous knockout mice and several mouse models with CNVs [ 54 , 55 , 57 , 58 , 88 , 91 ]. Common electrophysiological phenotypes include altered synaptic transmissions, such as diminished excitability indicated by reduced excitatory postsynaptic currents [ 55 , 58 , 60 , 75 , 79 , 82 , 85 , 88 , 91 ] or deficits in long-term potentiation [ 68 , 79 ], though some mice showed increased excitability or altered activities of other neuronal subtypes such as GABAergic neurons [ 70 , 84 ].…”

Section: Studies Of Etiologically Valid Mouse and Cellular Models Of ...mentioning

confidence: 99%

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

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Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.

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Section: Studies Of Etiologically Valid Mouse and Cellular Models Of ...mentioning

confidence: 99%

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

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“…Following the publication of the SCHEMA results and confirmation of SP4 as a schizophrenia risk gene, further investigations into Sp4 hypomorphic mice were conducted [44] . The hippocampal vacuolisation observed in these mice with reduced Sp4 expression was found to be associated with the deficits in LTP as well as the observed sensorimotor gating, learning, and memory deficits [44,57] .…”

Section: Glutamatergic System Dysregulationmentioning

confidence: 85%

“…Overall, these findings relating to SETD1A suggest that schizophrenia risk may be mediated by abnormal synaptic development and function, arising as a result of aberrant epigenetic modifications [57] .…”

Section: Chromatin Modificationmentioning

confidence: 90%

What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

Heinzer,

Curtis

2024

J Transl Genet Genom

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With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A , CACNA1G , CUL1 , GRIA3 , GRIN2A , HERC1 , RB1CC1 , SP4 , TRIO , XPO7 , and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.

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“…Based on our earlier observations that GluA1-deficient mice are models of impaired synaptic plasticity relevant to schizophrenia, 29 , 77 , 86 , 87 and that GluA2(Q/R) editing-deficient mice with drastically increased numbers of Ca 2+ -permeable AMPAR are associated with epilepsy, 88 , 89 the subsequent genetic analyses of neurological and neuropsychological patients have shown that GluA1, 2 and 3 AMPAR subunit mutations can all be associated with such disorders [e.g., 90 , 91 , 92 , 93 . From this perspective, it is of particular interest to describe the learning and memory processes that are disrupted, and those which are spared in the presence of defective AMPAR signaling.…”

Section: Discussionmentioning

confidence: 99%

Distinct effects of AMPAR subunit depletion on spatial memory

Eltokhi,

Bertocchi,

Rozov

et al. 2023

iScience

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Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human

Cited by 14 publications

References 51 publications

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

Distinct effects of AMPAR subunit depletion on spatial memory

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