Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia
Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia
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DOI：
10.1073/pnas.0405077101
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发表时间：
2004-08-24
影响因子：
11.1
通讯作者：
Weinberger, DR
中科院分区：
文献类型：
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作者：
Egan, MF;Straub, RE;Weinberger, DR
GRM 3是一个代谢型谷氨酸受体调节突触谷氨酸，是一个有希望的精神分裂症候选基因。在一项基于家族的关联研究中，一种常见的GRM 3单倍型与精神分裂症密切相关（P = 0.0001）。在该单倍型中，内含子2的单核苷酸多态性（SNP）4（hCV 11245618）的A等位基因略微过度传递给先证者（P = 0.02）。我们研究了这种SNP对与精神分裂症和谷氨酸神经传递风险相关的神经生物学特征的影响。SNP 4A等位基因与前额叶和海马功能的几项认知测试中表现较差相关。这种效应的生理基础进行了评估与功能性MRI，这表明相对有害的激活模式，在两个皮质区在控制受试者纯合子的SNP 4 A等位基因。接下来，我们研究了SNP 4对前额叶谷氨酸神经传递的两种间接测量的影响。前额叶N-乙酰天冬氨酸，在体内MRI测量相关的突触活动和组织谷氨酸密切相关，是较低的SNP 4 AA纯合子。在死后的人类前额叶皮层，AA纯合子有较低的神经胶质细胞谷氨酸转运蛋白EAAT 2的mRNA水平，这是一种由GRM 3调控的蛋白质，可严重调节突触谷氨酸。SNP 4对前额叶GRM 3 mRNA和蛋白水平的影响很小。重测序显示没有错义或剪接位点SNIPS，这表明内含子SNP 4或相关单倍型可能对GRM 3转录产生微妙的调节作用。这些汇聚的数据指向一个特定的分子途径，GRM 3基因型通过该途径改变谷氨酸神经传递、前额叶和海马生理学和认知，从而增加精神分裂症的风险。
GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. in a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNIPS, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.