The glutamate hypothesis of schizophrenia suggests that altered glutamatergic transmission occurs in this illness, although precise mechanisms of dysregulation remain elusive. AMPA receptors (AMPARs), a subtype of ionotropic glutamate receptor, are the main facilitators of fast, excitatory neurotransmission in the brain, and changes in AMPAR number or composition at synapses can regulate synaptic strength and plasticity. Prior evidence of abnormal expression of transmembrane AMPAR regulatory proteins (TARPs) in schizophrenia suggests defective trafficking of AMPARs, which we propose could lead to altered AMPAR expression at excitatory synapses. To test this hypothesis, we isolated subcellular fractions enriched for endoplasmic reticulum (ER) and synapses from anterior cingulate cortex (ACC) from schizophrenia (N = 18) and comparison (N = 18) subjects, and measured glutamate receptor subunits (GluA1, GluA2, GluA3, GluA4, NR1, NR2A, NR2B, and NR3A) and TARP member γ2 (stargazin) in homogenates and subcellular fractions by western blot analysis. We found decreased expression of stargazin and an increased ratio of GluA2:stargazin in ACC homogenates, while in the synapse fraction we identified a decrease in GluA1 and reduced ratios of GluA1:stargazin and GluA1:GluA2 in schizophrenia. The amount of stargazin in the ER fraction was not different, but the relative amount of ER/Total stargazin was increased in schizophrenia. Together, these findings suggest that associations between stargazin and AMPA subunits are abnormal, potentially affecting forward trafficking or synaptic stability of GluA1-containing AMPARs. These data provide evidence that altered interactions with trafficking proteins may contribute to glutamate dysregulation in schizophrenia.

中文翻译：

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精神分裂症前扣带皮层 AMPA 受体亚基定位

精神分裂症的谷氨酸假说表明，这种疾病中发生了谷氨酸能传递的改变，尽管失调的确切机制仍然难以捉摸。AMPA 受体 (AMPAR) 是离子型谷氨酸受体的一种亚型，是大脑中快速、兴奋性神经传递的主要促进剂，突触处 AMPAR 数量或组成的变化可以调节突触强度和可塑性。精神分裂症中跨膜 AMPAR 调节蛋白 (TARP) 异常表达的先前证据表明 AMPAR 的运输存在缺陷，我们认为这可能导致兴奋性突触处 AMPAR 表达的改变。为了检验这个假设，我们从精神分裂症 (N = 18) 和比较 (N = 18) 受试者的前扣带皮层 (ACC) 中分离出富含内质网 (ER) 和突触的亚细胞组分，并测量了谷氨酸受体亚基（GluA1、GluA2、GluA3、GluA4、 NR1、NR2A、NR2B 和 NR3A) 和 TARP 成员 γ2 (stargazin) 在匀浆和亚细胞组分中的蛋白质印迹分析。我们发现 ACC 匀浆中 stargazin 的表达降低和 GluA2:stargazin 的比例增加，而在突触部分中，我们发现精神分裂症中 GluA1 的减少和 GluA1:stargazin 和 GluA1:GluA2 的比例降低。ER 部分中 stargazin 的量没有差异，但 ER/Total stargazin 的相对量在精神分裂症中增加了。一起，这些发现表明 stargazin 和 AMPA 亚基之间的关联是异常的，可能影响含有 GluA1 的 AMPAR 的前向运输或突触稳定性。这些数据提供的证据表明，与运输蛋白的相互作用改变可能导致精神分裂症中的谷氨酸失调。